2-aminopyridine analogs as glucokinase activators

ABSTRACT

Provided are compounds that are useful in the treatment and/or prevention of diseases mediated by deficient levels of glucokinase activity, such as diabetes mellitus. Also provided are methods of treating or preventing diseases and disorders characterized by underactivity of glucokinase or which can be treated by activating glucokinase.

PRIORITY OF INVENTION

This application is a divisional of co-pending U.S. Ser. No. 13/191,994,filed Jul. 27, 2011, which is a divisional of U.S. Ser. No. 12/282,600,filed Oct. 28, 2008, now U.S. Pat. No. 8,022,223, which is a NationalStage Entry of PCT/US07/07444, filed Mar. 23, 2007, which claimspriority to U.S. Ser. No. 60/785,460, filed Mar. 24, 2006, all of whichare hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

Provided are compounds that are useful in the treatment and/orprevention of diseases mediated by deficient levels of glucokinaseactivity, such as diabetes mellitus, and methods of preparing suchcompounds. Also provided are methods of treating disease and disorderscharacterized by underactivation of glucokinase activity or which can betreated by activating glucokinase, comprising administering an effectiveamount of a compound of this invention.

BACKGROUND OF THE INVENTION

Diabetes mellitus comprises a group of syndromes characterized by aninability of the body to produce adequate insulin or to properly useinsulin. Most diabetes patients can be classified clinically as havingeither insulin-dependent diabetes mellitus (IDDM) ornon-insulin-dependent diabetes mellitus (NIDDM). Nearly all forms ofdiabetes mellitus result from either a decrease in the secretion andblood concentration of insulin or a decrease in the response of tissuesto insulin (insulin resistance), often associated with an elevated levelof hormones (e.g., glucagon) that act contrary to insulin. Suchabnormalities give rise to changes in carbohydrate, lipid and proteinmetabolism. The syndrome's hallmark is hyperglycemia; othercomplications can include cardiovascular disease, retinopathy,neuropathy, nephropathy, skin disorders and gastroparesis.

Diabetes mellitus affects millions of persons worldwide, including over18 million in the United States. It, is estimated that IDDM (Type Idiabetes), which results from the body's failure to produce insulin,accounts for 5-10% of the cases of diabetes diagnosed in the UnitedStates. The majority of diabetes patients in the United States arediagnosed with NIDDM (Type II diabetes), which results from insulinresistance combined with the inability of the pancreas to secretesufficient insulin to overcome such resistance. Type II diabetes occursin at least 5% of the United States population, and in 1996 alone NIDDMaffected 16 million people (Roman, S. H.; Harris, M. I., Endocrinologyand Metabolism Clinics of North America, 1997, 26.3, 443-474). Impairedglucose tolerance (IGT), a syndrome characterized by impaired glucoseprocessing that presents symptoms similar to a mild form of Type IIdiabetes, is even more prevalent, affecting 35 to 40 million adults inthe United States.

Diabetes is most frequently diagnosed either by the presentation of afasting plasma glucose of greater than or equal to 126 mg/dL on twooccasions, or by an oral glucose tolerance test (OGTT) with a 2 hourpost load value of greater than 200 mg/dL plus classic symptoms such aspolydipsia, polyphagia and/or polyuria (The Expert Committee on theDiagnosis and Classification of Diabetes Mellitus, Diabetes Care, 1998,21, S5-19). In the case of IGT, a fasting plasma glucose of less than126 mg/dL but a 2-hour post-oral glucose challenge lever greater than140 mg/dL is observed.

A primary goal in the treatment of each of these conditions is thereduction and control of blood glucose levels. The reduction ofhyperglycemia in insulin-dependent diabetes (IDDM) can attenuate thedevelopment of many of the attendant complications of IDDM (DiabetesControl and Complications Trial Research Group, New England J. Med.,1993, 329, 977-986). For example, tight control of blood glucose levelsthrough intensive insulin therapy can reduce the development ofretinopathy, nephropathy and neuropathy by >50% each in IDDM patients.These findings, together with the similarity of the pathologies seen inIDDM and NIDDM, suggest that control of blood glucose levels wouldproduce similar benefits in NIDDM patients (American DiabetesAssociation, Diabetes Care, 1998, 21, S88-90), as has been reported(Ohkubo, Y., et al., Diabetes Res. Clin. Pract. 1995, 28, 103-117).

Several methods to treat hyperglycemia have been attempted. Patientswith Type I diabetes receive insulin. In patients with Type. IIdiabetes, the pancreas secretes insulin, but in insufficient amounts toovercome the intrinsic insulin resistance of the disease. Theadministration of agents such as metformin (De Fronzo, R. A.; Goodman,A. M. N. Engl. J. Med., 1995, 333, 541-549; Bailey, C. J. Biguanides andNIDDM, Diabetes Care 1992, 15, 773-784) and glitazone (PPAR agonistclass of drugs; Willson, T. M., et al., J. Med. Chem. 1996, 39, 665-668)can at least partially ameliorate insulin resistance, but these agentsdo not promote insulin secretion. Treatment with certain sulfonylureashas been shown to promote insulin secretion by affecting an ion channel;however, the increase in insulin caused by this class of drugs is notglucose dependent or even glucose sensitive, and such treatment canactually raise the risk of overt hypoglycemia. DPP-IV inhibitors, suchas Januvia, or GLP or a GLP mimetic (such as Exedin), promote cAMPsecretion at the β-cell through an incretin mechanism, andadministration of these agents promotes insulin release in a glucosedependent manner (Vahl, T. P., D'Alessio, D. A., Expert Opinion onInvest. Drugs 2004, 13, 177-188). However, even with these potentialtreatments, it is difficult to achieve tight control of blood glucoselevels in NIDMM patients in accordance with the guidelines recommendedby the American Diabetes Association. Accordingly, there is significantdemand for novel therapeutic approaches that allow sufficient glycemiccontrol.

Possible approaches to glycemic control include enhancing clearance ofglucose from the blood and increasing the rate of glucose storage orutilization. Glucose enters most cells by a specific transport protein,where it is phosphorylated to form glucose-6-phosphate in a reactioncatalyzed by a hexokinase. Inside the cell, glucose-6-phosphate has oneof several fates: it can be broken down by the glycolytic pathway,converted into glycogen or it can be oxidized by the pentose phosphatepathway.

Glucokinase (GK) (ATP:D-hexose 6-phosphotransferase), one of the fourtypes of mammalian hexokinases (hexokinase IV), plays an essential rolein blood glucose homeostasis. Expression of glucokinase is largelylocalized in the liver and pancreatic β-cells, where several types ofglucokinase are expressed: these types differ in the sequence of the 15N-terminal amino acids due to differences in splicing, but theirenzymatic properties are virtually identical. Glucokinase is alsoexpressed in a population of neurons in the hypothalamus.

Unlike the enzymatic activities of the other three hexokinases (I, II,III), each of which becomes saturated at a glucose concentration ofbelow 1 mM, glucokinase has a K_(m) for glucose of 8 mM, which is closeto the physiological glucose level (5 mM). Thus, at lower glucoselevels, glucose is more rapidly utilized in brain, muscle and otherperipheral tissues—through conversion by a hexokinase other thanglucokinase—than in the liver. At elevated glucose levels, such as aftera meal or overnutrition (the postprandial glucose level can exceed 10-15mM), glucokinase-mediated glucose metabolism in the liver and pancreasis accelerated. Moreover, hexokinases I, II and III are inhibited byhigh concentrations of glucose-6-phosphate, lowering glucoseutilization, whereas glucokinase continues to catalyze utilization ofglucose even at high levels of glucose-6-phosphate.

In tissues where glucokinase is expressed, it plays an important role inglucose uptake and utilization: in the β-cell, the glucose-6-phosphateproduced is a necessary signal for insulin release; in the hypothalamusglucose-6-phosphate acts as a satiety signal and might contribute to thesecretion of enteroincretins; and in the liver, whereglucose-6-phosphate production by the action of glucokinase acts as amechanism for disposal of excessive glucose through storage as glycogen(Printz, R. L., et al., Annu. Rev. Nutr., 1993, 13, 463-496).Glucokinase-catalyzed glucose phosphorylation is the rate-limitingreaction for glycolysis in hepatocytes and pancreatic β-cells. In theliver, glucokinase determines the rates of both glucose uptake andglycogen synthesis, and it is also thought to be essential for theregulation of various glucose-responsive genes (Girard, J., et al.,Annu. Rev. Nutr., 1997, 17, 325-352). In both liver and pancreaticβ-cells, glucokinase is rate limiting for glucose utilization, andconsequently is a major component of the regulation of insulin secretionfrom the β-cell and glycogen storage in the liver. The control ofinsulin secretion and the control of glycogen storage are deficient indiabetes (DeFronzo, R. A., Diabetes, 1988, 37, 667-687).

The theoretical importance of glucokinase in diabetes is supported bystudies of genetic populations and genetic manipulation of animal modelsof NIDDM. Mutation of glucokinase to a less active form of the kinase isthe cause of the Maturity Onset of Diabetes in the Young (MODY-2)(Froguel, P., et al., New England J. Med., 1993, 328, 697-702; Bell, G.I., et al., Annual Rev. of Physiol., 1996, 58, 171-186). Conversely,humans with a glucokinase activation mutation are less prone tohyperglycemia and have increased insulin secretion in response to aglucose challenge (Christesen, H. B., et al., Diabetes, 2002, 51,1240-1246; Gloyn, A. L, et al., Diabetes, 2003, 52, 2433-2440; Glaser,B., et al., New England J. Med., 1998, 338, 226-230). Also, NIDDMpatients have been reported to have inappropriately low glucokinaseactivity. Furthermore, over expression of glucokinase in dietary orgenetic animal models of diabetes either prevents, ameliorates, orreverses the progress of pathological symptoms in the disease (Caro, J.F., et al., Hormone & Metabolic Res., 1995, 27, 19-22). For thesereasons, compounds that activate glucokinase have been sought by thepharmaceutical industry.

Substituted benzyl carbamoyl, substituted heterobenzyl carbamoyl,substituted phenyl carbamoyl, and substituted heteroaryl carbamoylcompounds have been disclosed as glucokinase activators. See, forexample, WO 03/000267, WO 03/015774, WO 04/045614, WO 04/046139, WO05/04480, WO 05/054200, WO 05/054233, WO 05/044801, WO 05/056530, WO03/080585, WO 04/076420, WO 04/081001, WO 04/063194, WO 04/050645, WO03/055482, WO 04/002481, WO 05/066145, WO 04/072031, WO 04/072066, U.S.Pat. No. 6,610,846, WO 00/058293, WO 03/095438, WO 01/44216, WO01/083465, WO 01/083478, WO 01/085706, WO 01/085707, WO 02/008209, WO02/014312, WO 02/046173, WO 02/048106, WO 03/095438, WO 04/031179, andWO 04/052869. These compounds either lower the K_(m) for glucose and/orincrease the V_(max), of glucokinase.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds that are activators ofglucokinase which are useful in the treatment of diseases and disordersthat would benefit from activation of glucokinase.

More specifically, one aspect of this invention provides compounds ofFormula I

and solvates, metabolites, salts and pharmaceutically acceptableprodrugs thereof, wherein L, Y, Z, G, R¹ and R² are as defined below.

The invention also provides pharmaceutical compositions comprising acompound of Formula I, or a solvate, metabolite, and solvate,metabolite, salt or pharmaceutically acceptable prodrugs thereof, and apharmaceutically acceptable carrier.

The inventive compounds may be used advantageously in combination withother known therapeutic agents. Accordingly, this invention alsoprovides pharmaceutical compositions comprising a compound of Formula Ior a solvate, metabolite, or pharmaceutically acceptable salt or prodrugthereof, in combination with a second therapeutic agent.

This invention also provides methods of preventing or treating a diseaseor disorder characterized by underactivation of glucokinase or which canbe treated by activating glucokinase in a mammal, comprisingadministrating to said mammal one or more compounds of Formula I, or ametabolite, solvate, or pharmaceutically acceptable salt or prodrugthereof, in an amount effective to treat said disease or disorder. Thecompounds of the present invention can be used, for example, asprophylactics or therapeutic agents for treating diseases or disordersmediated by deficient levels of glucokinase activity, including, but notlimited to, diabetes mellitus (type I and type II), impaired glucosetolerance, IFG (impaired fasting glucose) and IFG (impaired fastingglycemia), as well as other diseases and disorders characterized byunderactivation of glucokinase or which can be treated by activation ofglucokinase, such as those discussed below.

This invention also provides compounds of Formula I for use in therapy.

An additional aspect of the invention is the use of a compound ofFormula I for the preparation of a medicament for use as a glucokinaseactivator.

This invention further provides kits for the treatment or prevention ofa disease or disorder characterized by underactivation of glucokinase,said kit comprising a compound of Formula I, or a solvate, metabolite,or pharmaceutically acceptable salt or prodrug thereof, a container, andoptionally a package insert or label indicating a treatment. The kitsmay further comprise a second compound or formulation comprising asecond pharmaceutical agent useful for treating said disease ordisorder.

This invention further includes methods of preparing, methods ofseparating, and methods of purifying of the compounds of this invention.

Additional advantages and novel features of this invention shall be setforth in part in the description that follows, and in part will becomeapparent to those skilled in the art upon examination of the followingspecification or may be learned by the practice of the invention. Theadvantages of the invention may be realized and attained by means of theinstrumentalities, combinations, compositions, and methods particularlypointed out in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents which may be included within the scope ofthe present invention as defined by the claims. One skilled in the artwill recognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice of the presentinvention. The present invention is in no way limited to the methods andmaterials described. In the event that one or more of the incorporatedliterature and similar materials differs from or contradicts thisapplication, including but not limited to defined terms, term usage,described techniques, or the like, this application controls.

Definitions

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms, wherein the alkyl radical may be optionally substitutedindependently with one or more substituents described below. Examples ofalkyl groups include, but are not limited to, methyl (Me, —CH₃), ethyl(Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr,i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃),2-methyl-1-propyl (1-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl(n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl, 1-octyl, and the like.

In certain embodiments, the term “alkyl” refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to six carbonatoms, wherein the alkyl radical may be optionally substitutedindependently with one or more substituents described below.

The term “alkylene” as used herein refers to a linear or branchedsaturated divalent hydrocarbon radical of one to twelve carbon atoms,wherein the alkylene radical may be optionally substituted independentlywith one or more substituents described herein. Examples include, butare not limited to, methylene, ethylene, propylene, 2-methylpropylene,pentylene, and the like.

In certain embodiments, the term “alkylene” refers to a linear orbranched saturated divalent hydrocarbon radical of one to four carbonatoms, wherein the alkylene radical may be optionally substitutedindependently with one or more substituents described herein.

The term “alkenyl” as used herein refers to a linear or branched-chainmonovalent hydrocarbon radical of two to twelve carbon atoms with atleast one site of unsaturation, i.e., a carbon-carbon sp² double bond,wherein the alkenyl radical may be optionally substituted independentlywith one or more substituents described herein, and includes radicalshaving “cis” and “trans” orientations, or alternatively, “E” and “Z”orientations. Examples include, but are not limited to, ethylenyl orvinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), 1-buten-1-yl, 1-buten-2-yl, and thelike.

In certain embodiments, the term “alkenyl” as used herein refers to alinear or branched-chain monovalent hydrocarbon radical of two to sixcarbon atoms with at least one site of unsaturation, wherein the alkenylradical may be optionally substituted independently with one or moresubstituents described herein, and includes radicals having “cis” and“trans” orientations.

The term “alkenylene” as used herein refers to a linear or brancheddivalent hydrocarbon radical of two to twelve carbons containing atleast one double bond, wherein the alkenylene radical may be optionallysubstituted independently with one or more substituents describedherein. Examples include, but are not limited to, ethenylene,propenylene, and the like.

The term “alkenylene” includes, linear or branched divalent hydrocarbonradical of two to four carbons containing at least one double bond,wherein the alkenylene radical may be optionally substitutedindependently with one or more substituents described herein.

The term “alkynyl” as used herein refers to a linear or branchedmonovalent hydrocarbon radical of two to twelve carbon atoms with atleast one site of unsaturation, i.e., a carbon-carbon sp triple bond,wherein the alkynyl radical may be optionally substituted independentlywith one or more substituents described herein. Examples include, butare not limited to, ethynyl (—C≡CH), propynyl (propargyl, —CH₂C≡CH) andthe like.

In certain embodiments, the term “alkynyl” refers to a linear orbranched monovalent hydrocarbon radical of two to six carbon atoms withat least one carbon-carbon sp triple bond.

The term “alkynylene” as used herein refers to a linear or brancheddivalent hydrocarbon radical of two to twelve carbons containing atleast one triple bond, wherein the alkynylene radical may be optionallysubstituted independently with one or more substituents describedherein. Examples include, but are not limited to, ethynylene,propynylene, and the like.

In certain embodiments, the term “alkynylene” refers to a linear orbranched divalent hydrocarbon radical of two to four carbons containingat least one triple bond.

The terms “cycloalkyl,” “carbocycle,” “carbocyclyl” and “carbocyclicring” are used interchangeably and refer to a saturated or partiallyunsaturated cyclic hydrocarbon radical having from three to twelvecarbon atoms. The term “cycloalkyl” includes monocyclic and polycyclic(e.g., bicyclic and tricyclic) cycloalkyl structures, wherein thepolycyclic structures optionally include a saturated or partiallyunsaturated cycloalkyl fused to a saturated, partially unsaturated oraromatic cycloalkyl or heterocyclic ring. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, andthe like. Bicyclic carbocycles include those having 7 to 12 ring atomsarranged, for example, as a bicyclo [4,5], [5,5], [5,6] or [6,6] system,or as bridged systems such as bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. The cycloalkyl may beoptionally substituted independently with one or more substituentsdescribed herein.

“Aryl” as used herein means a monovalent aromatic hydrocarbon radical of6-20 carbon atoms derived by the removal of one hydrogen atom from asingle carbon atom of a parent aromatic ring system. Aryl includesbicyclic radicals comprising an aromatic ring fused to a saturated,partially unsaturated ring, or aromatic carbocyclic or heterocyclicring. Exemplary aryl groups include, but are not limited to, radicalsderived from benzene, naphthalene, anthracene, biphenyl, indene, indane,1,2-dihydronapthalene, 1,2,3,4-tetrahydronapthalene, and the like. Arylgroups may be optionally substituted independently with one or moresubstituents described herein.

The terms “heterocycle”, “heterocyclyl” and “heterocyclic ring” as usedherein are used interchangeably and refer to a saturated or partiallyunsaturated carbocyclic radical of 3 to 12 ring atoms in which at leastone ring atom is a heteroatom independently selected from nitrogen,oxygen and sulfur, the remaining ring atoms being C, where one or morering atoms may be optionally substituted independently with one or moresubstituents described below. The radical may be a carbon radical orheteroatom radical. The term “heterocycle” includes heterocycloalkoxy.“Heterocyclyl” also includes radicals where heterocycle radicals arefused with a saturated, partially unsaturated, or aromatic carbocyclicor heterocyclic ring. Examples of heterocyclic rings include, but arenot limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl,thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl,4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl,dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolylquinolizinyl and N-pyridyl ureas. Spiro moieties are also includedwithin the scope of this definition. The heterocycle may be C-attachedor N-attached where such is possible. For instance, a group derived frompyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).Further, a group derived from imidazole may be imidazol-1-yl(N-attached) or imidazol-3-yl (C-attached). Examples of heterocyclicgroups wherein 2 ring carbon atoms are substituted with oxo (═O)moieties are isoindoline-1,3-dionyl and 1,1-dioxo-thiomorpholiniyl. Theheterocycle groups herein are unsubstituted or, as specified,substituted in one or more substitutable positions with various groupsdescribed herein.

In certain embodiments, the term “heterocycle” includes bridgedheterocycles.

The term “heteroaryl” as used herein refers to a monovalent aromaticradical of a 5-, 6-, or 7-membered ring, and includes fused ring systems(at least one of which is aromatic) of 5-12 atoms, containing at leastone heteroatom independently selected from nitrogen, oxygen, and sulfur.Examples of heteroaryl groups include, but are not limited to,pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Spiromoieties are also included within the scope of this definition.Heteroaryl groups may be optionally substituted independently at one ormore substitutable positions with one or more substituents describedherein. Particular examples of heteroaryl groups include thiazolyl,thiadiazolyl, oxadiazolyl, oxazolyl, thiazolo[5,4-b]pyridinyl,thiazolo[5,4-b]pyrazinyl, and thiazolo[5,4-e][1,2,4]triazine.

By way of example and not limitation, carbon bonded heterocycles andheteroaryls are bonded at position 2, 3, 4, 5, or 6 of a pyridine,position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of apyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole ortetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole orthiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole,position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine,position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5,6, 7, or 8 of an isoquinoline. Further examples of carbon bondedheterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl,6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl,3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles andheteroaryls are bonded at position 1 of an aziridine, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, position 2 of an isoindole, or isoindoline, position 4 of amorpholine, and position 9 of a carbazole, or β-carboline. Still moretypically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl,1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

The term “halogen” as used herein means fluoro, chloro, bromo or iodo.

The term “a” as used herein means one or more.

As used herein, the terms “compound of this invention,” “compounds ofthe present invention” and “compounds of Formula I” include compounds ofFormula I and tautomers, resolved enantiomers, resolved diastereomers,racemic mixtures, solvates, metabolites, salts and prodrugs thereof,including pharmaceutically acceptable salts and prodrugs.

In general, the various moieties or functional groups of the compoundsof this invention may be optionally substituted by one or moresubstituents. Examples of substituents suitable for purposes of thisinvention include, but are not limited to, oxo, halogen, CN, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, V_(n)—NR″SO₂R′,V_(n)—SO₂NR′R″, V_(n)—C(═O)R′, V_(n)—C(═O)OR′, V_(n)—OC(═O)R′,V_(n)—NR″C(═O)OR′, V_(n)—NR″C(═O)R′, V_(n)—C(═O)NR′R″, V_(n)—NR′R″,V_(n)—NR′″C(═O)N′R″, V_(n)—OR′, V_(n)—SR′, V_(n)—S(O)R′, V_(n)—S(O)₂R′,alkyl, alkenyl, alkynyl, V_(n)-cycloalkyl; V_(n)-heterocyclyl,V_(n)-aryl, and V_(n)-heteroaryl, where R′, R″ and R′″ are independentlyH, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl.

It is to be understood that in instances where two or more radicals areused in succession to define a substituent attached to a structure, thefirst named radical is considered to be terminal and the last namedradical is considered to be attached to the structure in question. Thus,for example, an arylalkyl radical is attached to the structure inquestion by the alkyl group,

Glucokinase Activators

The present invention provides compounds, and pharmaceuticalformulations thereof, that are useful in the treatment of diseases,conditions and/or disorders characterized by underactivation ofglucokinase or which can be treated by activation of glucokinase.

One aspect of the invention provides compounds of Formula I

and tautomers, resolved enantiomers, resolved diastereomers, racemicmixtures, solvates, metabolites, salts and pharmaceutically acceptableprodrugs thereof, wherein:

L is O, S, C(═O) or CHR¹⁴;

Y is N or CR⁴;

Z is N or CR³, wherein at least one of G or Z is not N;

G is N or CR¹¹;

R¹ is a heteroaryl ring represented by the formula

D1-D²

D¹ is S, O, or N;

D² is N or CR¹²;

D³ is S, O or CR¹³;

R² is aryl, heteroaryl, saturated or partially unsaturated cycloalkyl,or saturated or partially unsaturated heterocyclyl, wherein said aryl,heteroaryl, cycloalkyl and heterocyclyl are monocyclic or bicyclic andare optionally substituted with one or more groups independentlyselected from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturated andpartially unsaturated C₃-C₆ cycloalkyl, saturated and partiallyunsaturated C₁-C₆ heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, CF₃, CN,NO₂, OR⁶, C(═O)R⁶, C(═O)OR⁶, OC(═O)R⁶, —O(CH₂)_(n)C(═O)OR⁶,O(CH₂)_(n)C(═O)NR⁶R⁷, C(═O)NR⁶R⁷, NR⁶R⁷, NR⁶C(═O)R⁷, SR⁶, S(O)R⁶, andS(O)₂R⁶, and wherein said alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl are optionally substituted with oneor more groups independently selected from oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, saturated and partially unsaturated C₃-C₆V_(n)-cycloalkyl, saturated and partially unsaturated C₁-C₆V_(n)-heterocyclyl, V_(n)-aryl, V_(n)-heteroaryl, V_(n)—F, V_(n)—C₁,V_(n)—Br, V_(n)—I, V_(n)—CF₃, V_(n)—CN, V_(n)—OR⁸, V_(n)—C(═O)R⁸,V_(n)—C(═O)OR⁸, V_(n)—OC(═O)R⁸, V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹,V_(n)—NR⁸C(═O)R⁹, V_(n)—SR⁸, V_(n)—S(O)R⁸, and V_(n)—S(O)₂R⁸;

R³ is H, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, saturated orpartially unsaturated C₃-C₁₂ cycloalkyl, saturated or partiallyunsaturated C₁-C₁₂ heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, CN,OR⁶, C(═O)R⁶, C(═O)OR⁶, OC(═O)R⁶, C(═O)NR⁶R⁷, —OC(═O)NR⁶R⁷, OC(═S)NR⁶R⁷,NR⁶R⁷, NR⁶C(═O)R⁷, SR⁶, S(O)R⁶, S(O)₂R⁶ or S(O)₂NR⁶R⁷, wherein saidalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroarylare optionally substituted with one or more groups independentlyselected from oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturatedand partially unsaturated C₃-C₆ cycloalkyl, saturated and partiallyunsaturated C₁-C₆ heterocyclyl, V_(n)-aryl, V_(n)-heteroaryl, V_(n)—F,V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—CF₃, V_(n)—CN, V_(n)—OR⁸,V_(n)—C(═O)R⁸, V_(n)—C(═O)OR⁸, V_(n)—OC(═O)R⁸, V_(n)—C(═O)NR⁸R⁹,V_(n)—NR⁸R⁹, V_(n)—NR⁸C(═O)R⁹, V_(n)—SR⁸, V_(n)—S(O)R⁸, V_(n)—S(O)₂R⁸and V_(n)—S(O)₂NR⁸R⁹;

R⁴ is H, methyl, ethyl, F, Cl, Br, I, CF₃, CHF₂ or CH₂F;

R⁶ and R⁷ are independently H, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂alkynyl, saturated or partially unsaturated C₃-C₁₂ cycloalkyl, saturatedor partially unsaturated C₁-C₁₂ heterocyclyl, V_(n)-aryl, orV_(n)-heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl and heteroaryl portions are optionally substitutedwith one or more groups independently selected from CF₃, oxo, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturated and partially unsaturatedC₃-C₆ cycloalkyl, saturated and partially unsaturated C₁-C₆ heterocyclyl[optionally substituted with C(O)O(1-6C alkyl), (1-6C)alkyl or (1-6Calkyl)OH], V_(n)-aryl, V_(n)-heteroaryl, V_(n)—F, V_(n)—C₁, V_(n)—Br,V_(n)—I, V_(n)—CF₃, V_(n)—CN, V_(n)—OR⁸, V_(n)—C(═O)R⁸, V_(n)—C(═O)OR⁸,V_(n)—OC(═O)R⁸, V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹, V_(n)—NR⁸C(═O)R⁹,V_(n)—SR⁸, V_(n)—S(O)R⁸, V_(n)—S(O)₂R⁸, V_(n)—S(O)₂NR⁸R⁹, and (C₁-C₆alkyl)OH;

or R⁶ and R⁷ together with the atoms to which they are attached form asaturated or partially unsaturated heterocyclic ring, wherein saidheterocyclic ring optionally comprises one or more additional ringheteroatoms independently selected from N, O or S, wherein saidheterocyclic ring is optionally substituted with one or more groupsindependently selected from oxo, V_(n)—F, V_(n)—Cl, V_(n)—Br, V_(n)—I,V_(n)—OR⁸, V_(n)—C(═O)OR⁸, V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹,V_(n)—NR⁸C(═O)R⁹, V_(n)—NR⁸C(═O)NR⁹R¹⁰, C₁-C₆ alkyl, C₂-C₆ alkenyl, andC₂-C₆ alkynyl;

R⁸, R⁹ and R¹⁰ are independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, saturated and partially unsaturated C₃-C₆ cycloalkyl, saturatedand partially unsaturated C₁-C₆ heterocyclyl, aryl or heteroaryl,wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl andheteroaryl are optionally substituted with one or more groupsindependently selected from oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, saturated and partially unsaturated C₃-C₆ cycloalkyl, saturatedand partially unsaturated C₁-C₆ heterocyclyl, V_(n)-aryl,V_(n)-heteroaryl, V_(n)—F, V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—OR^(a),V_(n)—NR^(a)R^(b), V_(n)—C(═O)OR^(a), V_(n)—C(═O)NR^(a)R^(b), andV_(n)—NR^(a)C(═O)R^(b),

or R⁸ and R⁹ together with the atoms to which they are attached form asaturated or partially unsaturated heterocyclic ring, wherein saidheterocyclic ring optionally comprises one or more additional ringheteroatoms independently selected from N, O or S, wherein saidheterocyclic ring is optionally substituted with one or more groupsindependently selected from oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, V_(n)—F, V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—OR^(a), andV_(n)—CN,

or R⁹ and R¹⁰ together with the atoms to which they are attached form asaturated or partially unsaturated heterocyclic ring, wherein saidheterocyclic ring optionally comprises one or more additional ringheteroatoms independently selected from N, O or S, wherein saidheterocyclic ring is optionally substituted with one or more groupsindependently selected from oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, V_(n)—F, V_(n)—C₁, V_(n)—Br, V_(n)—I, V_(n)—OR^(a), andV_(n)—CN;

R¹¹ is H, methyl, ethyl, F, Cl, Br, I, CF₃, CHF₂, CH₂F, OH, O—(C₁-C₄alkyl), or NH₂;

R¹² and R¹³ are independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, saturated and partially unsaturated C₃-C₆ cycloalkyl, saturatedand partially unsaturated C₁-C₆ heterocyclyl, CH₂-heterocyclyl, aryl,heteroaryl, (1-3C alkyl)heteroaryl, (CH₂)_(n)(CR^(x)R^(y))C(O)NR⁸R⁹, F,Cl, Br, I, CF₃, CN, OR⁶, C(═O)R⁶, C(═O)OR⁶, OC(═O)R⁶, C(═O)NR⁶R⁷, NR⁶R⁷,NR⁶C(═O)R⁷, SR⁶, S(O)R⁶, S(O)₂R⁶, wherein said alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substitutedwith one or more groups independently selected from oxo, V_(n)—F,V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—CF₃, V_(n)—CN, V_(n)—OR⁸,V_(n)—C(═O)OR⁸, V_(n)—OC(═O)R⁵, V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹,V_(n)—NR⁸C(═O)R⁹, C(O)(C₁-C₆ alkyl), C(O)-heterocycle [optionallysubstituted with O—(C₁-C₆ alkyl], SR^(a), SO₂R^(f), SO₂NR^(c)R^(e),C(O)(C₁-C₆ alkyl)NR^(c)Rd^(d), C(O)(C₁-C₆ alkyl)OR^(c),C(O)CH₂C(O)(C₁-C₆ alkyl), C(═O)CHR^(g)NHC(═O)(C₁-C₆ alkyl),C(═O)CH₂OC(═O)(C₁-C₆ alkyl), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,saturated and partially unsaturated C₃-C₆ cycloalkyl, saturated andpartially unsaturated C₁-C₆ heterocyclyl, V_(n)-aryl, andV_(n)-heteroaryl, wherein said heterocyclyl is optionally substitutedwith one or more oxo,

or R¹² and R¹³ together with the atoms to which they are attached form asaturated, partially unsaturated or aromatic carbocyclic or heterocyclicring, wherein said carbocyclic and heterocyclic rings are optionallysubstituted with one or more groups independently selected from C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturated and partially unsaturatedC₃-C₆ cycloalkyl, saturated and partially unsaturated C₁-C₆heterocyclyl, aryl, heteroaryl, oxo, F, Cl, Br, I, CF₃, CN, OR⁶,C(═O)R⁶, C(═O)OR⁶, OC(═O)R⁶, C(═O)NR⁶R⁷, NR⁶R⁷, NR⁶C(═O)R⁷, SR⁶, S(O)R⁶,S(O)₂R⁶ and SO₂NR⁶R⁷, wherein said alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl and heteroaryl are optionally substituted with one ormore groups independently selected from oxo, V_(n)—F, V_(n)—C₁,V_(n)—Br, V_(n)—I, V_(n)—CF₃, V_(n)—CN, V_(n)—OR⁸, V_(n)—C(═O)OR⁸,V_(n)—OC(═O)R⁸, V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹, V_(n)—NR⁸C(═O)R⁹, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturated and partially unsaturatedC₃-C₆ cycloalkyl, saturated and partially unsaturated C₁-C₆heterocyclyl, V_(n)-aryl, and V_(n)-heteroaryl;

R¹⁴ is H, methyl, ethyl or OH;

R^(a) and R^(b) are independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, saturated and partially unsaturated C₃-C₆ cycloalkyl, saturatedand partially unsaturated C₁-C₆ heterocyclyl, V_(n)-aryl, orV_(n)-heteroaryl, wherein said alkyl, alkenyl, alkynyl, saturated orpartially unsaturated V_(n)-cycloalkyl, saturated or partiallyunsaturated V_(n)-heterocyclyl, V_(n)-aryl, and V_(n)-heteroaryl areoptionally substituted with one or more OH;

each R^(c), R^(e) and R^(g) is independently H or C₁-C₆ alkyl;

R^(d) is H, C₁-C₆ alkyl or C(O)O(C₁-C₆ alkyl);

R^(f) is C₁-C₆ alkyl or (C₁-C₆ alkyl)NH₂;

R^(x) is H or C₁-C₆ alkyl;

R^(y) is H, C₁-C₆ alkyl, or —O(C₁-C₆ alkyl);

V is alkylene having from 1 to 12 carbons, or alkenylene or alkynyleneeach having from 2 to 12 carbons, wherein said alkylene, alkenylene, oralkynylene are optionally substituted with one or more groupsindependently selected from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,saturated and partially unsaturated C₃-C₆ cycloalkyl, saturated andpartially unsaturated C₁-C₆ heterocyclyl, aryl, heteroaryl, F, Cl, Br,I, CF₃, cyano, OR⁸, C(═O)OR⁸, OC(═O)R⁸, C(═O)NR⁸R⁹, NR⁸R⁹, (C₁-C₆alkyl)NR^(c)R^(e); and NR⁸C(═O)R⁹; and

n is 0 or 1.

In certain embodiments, R⁶ and R⁷ are optionally substituted with one ormore groups independently selected from oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, saturated and partially unsaturated C₃-C₆ cycloalkyl,saturated and partially unsaturated C₁-C₆ heterocyclyl, V_(n)-aryl,V_(n)-heteroaryl, V_(n)—F, V_(n)—C₁, V_(n)—Br, V_(n)—I, V₁—CF₃,V_(n)—CN, V_(n)—OR⁸, V_(n)—C(═O)R⁸, V_(n)—C(═O)OR⁸, V_(n)—OC(═O)R⁸,V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹, V_(n)—NR⁸C(═O)R⁹, V_(n)—SR⁸,V_(n)—S(O)R⁸, V_(n)—S(O)₂R⁸, and V_(n)—S(O)₂NR⁸R⁹.

In certain embodiments, R¹² and R¹³ are independently H, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturated and partially unsaturated C₃-C₆cycloalkyl, saturated and partially unsaturated C₁-C₆ heterocyclyl,aryl, heteroaryl, F, Cl, Br, I, CF₃, CN, OR⁶, C(═O)R⁶, C(═O)OR⁶,OC(═O)R⁶, C(═O)NR⁶R⁷, NR⁶R⁷, NR⁶C(═O)R⁷, SR⁶, S(O)R⁶ or S(O)₂R⁶, whereinsaid alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl andheteroaryl are optionally substituted with one or more groupsindependently selected from oxo, V_(n)—F, V_(n)—C₁, V_(n)—Br, V_(n)—I,V_(n)—CF₃, V_(n)—CN, V_(n)—OR⁸, V_(n)—C(═O)OR⁸, V_(n)—OC(═O)R⁸,V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹, V_(n)—NR⁸C(═O)R⁹, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, saturated and partially unsaturated C₃-C₆cycloalkyl, saturated and partially unsaturated C₁-C₆ heterocyclyl,V_(n)-aryl, and V_(n)-heteroaryl, wherein said heterocyclyl isoptionally substituted with one or more oxo.

In certain embodiments of compounds of Formula I, G is R¹¹.

In certain embodiments of compounds of Formula I, R¹¹ is hydrogen.

In certain embodiments of compounds of Formula I, Y is N.

In other embodiments, Y is CR⁴. In certain embodiments, R⁴ is H.

In certain embodiments of compounds of Formula I, L is O.

In certain embodiments of compounds of Formula I, L is S.

In certain embodiments of compounds of Formula I, L is CHR¹⁴. In certainembodiments, R¹⁴ is H.

The compounds of Formula I include compounds having the Formula Ia:

and tautomers, resolved enantiomers, resolved diastereomers, racemicmixtures, solvates, metabolites, salts and pharmaceutically acceptableprodrugs thereof, wherein:

L is O, S, or CH₂;

Y is N or CH; D² is N or CR²;

R² is aryl, heteroaryl, saturated or partially unsaturated cycloalkyl,or saturated or partially unsaturated heterocyclyl, wherein said aryl,heteroaryl, cycloalkyl and heterocyclyl are monocyclic or bicyclic andare optionally substituted with one or more groups independentlyselected from C₁-C₆ alkyl, (C₁-C₆ alkyl)OH, C₁-C₈ heterocyclyl, F, Cl,Br, CF₃, CN, NO₂, OR⁶, C(═O)R⁶, C(═O)OR⁶, C(═O)NR⁶R⁷, S(O)₂R⁶,C(O)CH₂NH₂, and C(O)CH₂NR^(a)R^(b);

R³ is H, C₁-C₁₂ alkyl, aryl, heteroaryl, F, Cl, Br, OR⁶, or SR⁶, whereinsaid alkyl, aryl and heteroaryl are optionally substituted with one ormore groups independently selected from C₁-C₆ alkyl, C₂-C₆ alkenyl,saturated and partially unsaturated C₁-C₆ heterocyclyl, V_(n)—OR⁸,V_(n)—C(═O)OR⁸, and V_(n)—NR⁸R⁹;

R⁶ and R⁷ are independently H, C₁-C₁₂ alkyl, saturated or partiallyunsaturated C₃-C₁₂ cycloalkyl, saturated or partially unsaturated C₁-C₁₂heterocyclyl, V_(n)-aryl, or V_(n)-heteroaryl, wherein said alkyl,cycloalkyl, heterocyclyl, aryl and heteroaryl portions are optionallysubstituted with one or more groups independently selected from C₁-C₆alkyl, saturated and partially unsaturated C₁-C₆ heterocyclyl[optionally substituted with C(O)O(C₁-C₆ alkyl) or (C₁-C₆ alkyl)OH],aryl, heteroaryl, F, Cl, Br, I, CN, OR⁸, C(═O)R⁸, C(═O)OR⁸, C(═O)NR⁸R⁹,NR⁸R⁹, NR⁸C(═O)R⁹ or (C₁-C₆ alkyl)OH,

or R⁶ and R⁷ together with the atoms to which they are attached form asaturated or partially unsaturated heterocyclic ring, wherein saidheterocyclic ring optionally comprises one or more additional ringheteroatoms independently selected from N, O or S;

R⁸, R⁹ and R¹⁰ are independently H, C₁-C₆ alkyl, or saturated andpartially unsaturated C₁-C₆ heterocyclyl, wherein said alkyl andheterocyclyl are optionally substituted with one or more groupsindependently selected from C₁-C₆ alkyl, saturated and partiallyunsaturated C₁-C₆ heterocyclyl, OR^(a), NR^(a)R^(b), C(═O)OR^(a) andC(═O)NR^(a)R^(b),

or R⁸ and R⁹ together with the atoms to which they are attached form asaturated or partially unsaturated heterocyclic ring;

or R⁹ and R¹¹ together with the atoms to which they are attached form asaturated or partially unsaturated heterocyclic ring;

R¹² is H or C₁-C₆ alkyl;

R¹³ is H, C₁-C₆ alkyl, saturated and partially unsaturated C₃-C₆cycloalkyl, saturated and partially unsaturated C₁-C₆ heterocyclyl,CH₂-heterocyclyl, aryl, heteroaryl, (1-3C alkyl)heteroaryl, or(CH₂)_(n)(CR^(x)R^(y))C(O)NR⁸R⁹, wherein said alkyl, alkenyl, alkynyl,cycloalkyl, CH₂-heterocyclyl, heterocyclyl, aryl, heteroaryl and (1-3Calkyl)heteroaryl are optionally substituted with one or more groupsindependently selected from oxo, F, Cl, CF₃, CN, OR⁸, C(═O)OR⁸,C(═O)NR⁸R⁹, NR⁸R⁹, C(O)(C₁-C₆ alkyl), C(O)-heterocycle [optionallysubstituted with O—(C₁-C₆ alkyl) or oxo], SR^(a), SO₂R^(f),SO₂NR^(c)R^(e), C(O)(C₁-C₆ alkyl)NR^(c)Rd^(d), C(O)(C₁-C₆ alkyl)OR^(c),C(O)CH₂C(O)(C₁-C₆ alkyl), C(═O)CHR^(g)NHC(═O)(C₁-C₆ alkyl),C(═O)CH₂OC(═O)(C₁-C₆ alkyl), C₁-C₆ alkyl, 5-6 membered heterocycle(optionally substituted with oxo) and aryl,

or R¹² and R¹³ together with the atoms to which they are attached forman heteroaryl ring;

R^(a) and R^(b) are independently H, C₁-C₆ alkyl, saturated or partiallyunsaturated C₁-C₆ heterocyclyl;

each R^(c), R^(e) and R^(g) is independently H or C₁-C₆ alkyl;

R^(d) is H, C₁-C₆ alkyl or C(O)O(C₁-C₆ alkyl);

R^(f) is C₁-C₆ alkyl or (C₁-C₆ alkyl)NH₂;

V is alkylene having from 1 to 4 carbons, or alkenylene having from 2 to4 carbons, wherein said alkylene and alkenylene are optionallysubstituted with C₁-C₆ alkyl, O(C₁-C₆ alkyl), or (C₁-C₆alkyl)NR^(c)R^(e); and

n is 0 or 1.

Exemplary embodiments of R¹ include, but are not limited to, heteroarylrings

wherein R²⁰ is H, alkyl, alkenyl, alkynyl, saturated or partiallyunsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl,aryl, heteroaryl, F, Cl, Br, I, CF₃, CN, OR⁶, C(═O)R⁶, C(═O)OR⁶,OC(═O)R⁶, C(═O)NR⁶R⁷, NR⁶R⁷, NR⁶C(═O)R⁷, SR⁶, S(O)R⁶, S(O)₂R⁶ orSO₂NR⁶R⁷, wherein said alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl and heteroaryl are optionally substituted with one ormore groups independently selected from oxo, V_(n)—F, V_(n)—C₁,V_(n)—Br, V_(n)—I, V_(n)—CF₃, V_(n)—CN, V_(n)—OR⁸, V_(n)—C(═O)OR⁸,V_(n)—OC(═O)R⁸, V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹, V_(n)—NR⁸C(═O)R⁹, alkyl,alkenyl, alkynyl, saturated and partially unsaturated V_(n)-cycloalkyl,saturated and partially unsaturated V_(n)-heterocyclyl, V_(n)-aryl, andV_(n)-heteroaryl,

and each R²⁰ is independent of the other.

In certain embodiments, R¹ is

wherein R¹² and R¹³ are as defined herein.

In particular embodiments, R²⁰ is H.

In other embodiments, R′ is

In certain embodiments, R¹² and R¹³ are independently selected from H,alkyl; or cycloalkyl, wherein said alkyl and cycloalkyl are optionallysubstituted. For example, in certain embodiments R¹² and R¹³ areindependently selected from H, methyl, ethyl, isopropyl, butyl,isobutyl, cyclopropyl, CH₂CH₂COOMe, CH₂COOH, and CH₂CH₂COOH.

In certain embodiments, R¹² is H or C₁-C₆ alkyl.

In certain embodiments, R¹² is H.

In other embodiments, R¹³ is selected from H, C₁-C₆ alkyl, cycloalkyl,heterocyclyl, CH₂-heterocyclyl, aryl, heteroaryl, (1-3Calkyl)heteroaryl, or (CH₂)_(m)(CR^(x)R^(y))C(O)NR⁸R⁹, wherein saidalkyl, cycloalkyl, heterocyclyl, CH₂-heterocyclyl, aryl, heteroaryl, and(1-3C alkyl)heteroaryl are optionally substituted with one or moregroups independently selected from oxo, F, Cl, CF₃, CN, OR⁸, C(═O)OR⁸,C(═O)NR⁸R⁹, NR⁸R⁹, C(O)(C₁-C₆ alkyl), C(O)-heterocycle [optionallysubstituted with O—(C₁-C₆ alkyl], SR^(a), SO₂R^(f), SO₂NR^(c)R^(e),C(O)(C₁-C₆ alkyl)NR^(c)Rd^(d), C(O)(C₁-C₆ alkyl)OR^(e),C(O)CH₂C(O)(C₁-C₆ alkyl), C(═O)CHR^(g)NHC(═O)(C₁-C₆ alkyl),C(═O)CH₂C(═O)(C₁-C₆ alkyl), C₁-C₆ alkyl, C₁-C₆ heterocyclyl (optionallysubstituted with oxo), and aryl.

For example, in certain embodiments R¹³ is selected from H, C₁-C₆ alkyl,chloro(C₁-C₆ alkyl), CF₃, (3-6C)cycloalkyl, (C₁-C₆ alkyl)CN, (C₁-C₆alkyl)CO₂R⁸, (C₁-C₆ alkyl)SR^(a), (C₁-C₆ alkyl)SO₂R^(f), (C₁-C₆alkyl)aryl, (C₁-C₆ alkyl)OR^(B), (C₁-C₆ alkyl)NR⁸R⁹,(CH₂)_(n)(CR^(x)R^(y))C(O)NR⁸R⁹, (CH₂)(CR^(x)R^(y))C(O)NH—N═CHNR⁸R⁹,(C₁-C₆ alkyl)C(O)-heterocyclyl, aryl, heteroaryl, (C₁-C₆ alkyl)hetAr¹,CH₂(CR^(x)R^(y))C(O)OR⁸, CH₂(CR^(x)R^(y))C(O)heterocyclyl [optionallysubstituted with one or two groups selected from O—(C₁-C₆ alkyl) andoxo], CH₂CH(CO₂H)—CH₂CH₂NHR^(a), hetCyc¹ and CH₂ hetCyc², wherein:

R^(x) and R^(y) are independently H, methyl or OMe,

hd n is 0 or 1,

hetCyc¹ is a heterocyclic ring optionally substituted with one or moregroups independently selected from C₁-C₆ alkyl, C(O)(C₁-C₆ alkyl),(C₁-C₆ alkyl)OH, C(O)O(C₁-C₆ alkyl), C(O)(C₁-C₆ alkyl)NR^(c)R^(d),C(O)(C₁-C₆ alkyl)OR^(c), C(O)CH₂C(O)(C₁-C₆ alkyl), C(O)NR^(a)R^(b),SO₂NR^(c)R^(e), SO₂R^(f), C(═O)CHR^(g)NHC(═O)(C₁-C₆ alkyl), andC(═O)CH₂C(═O)(C₁-C₆ alkyl).

hetCyc² is a heterocyclic ring optionally substituted with one or moregroups independently selected from C₁-C₆ alkyl, C(O)(C₁-C₆ alkyl),C(O)O(C₁-C₆ alkyl), and oxo, and

hetAr¹ is a heteroaryl ring optionally substituted with C₁-C₆ alky, OHor CF₃,

and R^(a), R^(b), R^(c), R^(d), R^(e) and R^(f) are as defined herein.

Examples of R¹³ when represented by C₁-C₆ alkyl include methyl, ethyl,isopropyl, isobutyl, and butyl.

Examples R¹³ when represented by chloro(C₁-C₆ alkyl) include alkylgroups wherein any one of the hydrogens is replaced with a chloro group.A particular example is CH₂Cl.

Examples of R¹³ when represented by (3-6C)cycloalkyl include cycloalkyland cyclohexyl.

Examples of R¹³ when represented by (C₁-C₆ alkyl)CN include alkyl groupswherein any one of the hydrogens is replaced with a nitrile group. Aparticular example is CH₂CN.

Examples of R¹³ when represented by (C₁-C₆ alkyl)CO₂R⁸ include alkylgroups wherein any one of the hydrogens is replaced with a CO₂R⁸ group.In certain embodiments, R⁸ is H or C₁-C₆ alkyl. Particular values of R¹³include CH₂CH₂CO₂H, CH₂CH₂CO₂Me, CH₂CO₂H, C(CH₃)₂CO₂H, CH₂C(CH₃)₂CO₂H,and C(CH₃)₂CH₂CO₂H.

Examples of R¹³ when represented by (C₁-C₆ alkyl)SR^(a) include alkylgroups wherein any one of the hydrogens is replaced with a SR^(a) group.In certain embodiments, R^(a) is C₁-C₆ alkyl, aryl or heteroaryl.Examples of heteroaryl groups include 5-membered rings having 1-3 atomsindependently selected from N and O (provide the ring does not containan O—O bond). In certain embodiments, the heteroaryl is substituted withC₁-C₆ alkyl. Particular values of R¹² and R¹³ when represented by (C₁-C₆alkyl)SR^(a) include CH₂CH₂SMe, CH₂SPh andCH₂—S-(2-methyl-1,3,4-oxadiazol-5-yl).

Examples of R¹³ when represented by (C₁-C₆ alkyl)SO₂R^(f) include alkylgroups wherein any one of the hydrogens is replaced with a SO₂R^(f)group. In certain embodiments, R^(f) is (C₁-C₆ alkyl). Particular valuesof R¹² and R¹³ include CH₂CH₂SO₂Me.

Examples of R¹³ when represented by (C₁-C₆ alkyl)aryl include CH₂Ph andCH₂CH₂Ph.

Examples of R¹³ when represented by (C₁-C₆ alkyl)OR⁸ include alkylgroups wherein any one of the hydrogens is replaced with a OR⁸ group. Incertain embodiments, R⁸ is aryl or heteroaryl. Examples of heteroarylgroups include 5-membered rings having 1-3 atoms independently selectedfrom N and O (provide the ring does not contain an O—O bond). In certainembodiments, the heteroaryl ring is substituted with one or more groupsindependently selected from C₁-C₆ alkyl and CF₃. Particular values ofR¹³ when represented by (C₁-C₆ alkyl)OR⁸ include CH₂OPh andCH₂O-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl).

Examples of R¹³ when represented by (C₁-C₆ alkyl)NR⁸R⁹ include alkylgroups wherein any one of the hydrogens is replaced with a NR⁸R⁹ group.In certain embodiments, R⁸ is H or methyl and R⁹ is aryl or heteroaryl.Examples of heteroaryl groups include 5-membered rings having 1-3 atomsindependently selected from N and O (provide the ring does not containan O—O bond). In certain embodiments, the heteroaryl ring is substitutedwith C₁-C₆ alkyl. Particular values of R¹² and R¹³ when represented by(C₁-C₆ alkyl)NR⁸R⁹ include CH₂NHPh andCH₂NH(2-methyl-1,3,4-oxadiazol-5-yl).

In certain embodiments, R¹³ are an alkyl group that is substituted withtwo or three groups independently selected from C₁-C₆ alkyl, O(C₁-C₆alkyl) and NR⁸R⁹. In one embodiment, R¹² and R¹³ can be represented bythe formula (CH₂)_(n)(CR^(x)R^(y))C(O)NR⁸R⁹ wherein R^(x) and R^(y) areindependently H, Me or OMe and n is 0 or 1.

Examples of R¹³ when represented by (CH₂)_(n)(CR^(x)R^(y))C(O)NR⁸R⁹include groups wherein R⁸ and R⁹ are independently H or (C₁-C₆ alkyl),and R^(x) and R^(y) are H. Particular values include CH₂CH₂C(O)NHMe,CH₂CH₂C(O)NMe₂, CH₂C(O)NHMe, and CH₂C(O)NMe₂.

Additional examples of R¹³ when represented by(CH₂)_(n)(CR^(x)R^(y))C(O)NR⁸R⁹ include groups wherein R⁸ is H or Me, R⁹is (C₁-C₆ alkyl)OH or (C₁-C₆ alkyl)O(C₁-C₆ alkyl), R^(x) is H or Me, andR^(y) is H, Me, or OMe. Particular values include CH₂CH₂C(O)NHCH₂CH₂OMe,CH₂CH₂C(O)NHCH₂CH₂OH, CH₂C(O)NHCH₂CH₂OMe, CH₂C(O)NHCH₂CH₂OH,CH₂C(CH₃)₂C(O)NHCH₂CH₂OH, CH₂C(CH₃)(OMe)C(O)NHCH₂CH₂OH, andCH₂C(CH₃)(OMe)C(O)NHCH₂CH₂OMe.

Additional examples of R¹³ when represented by(CH₂)_(n)(CR^(x)R^(y))C(O)NR⁸R⁹ include groups wherein Rx and R^(y) areH, R⁸ is H or Me, and R⁹ is (C₁-C₆ alkyl)NR^(a)R^(b). In certainembodiments, R^(a) and R^(b) are independently H or C₁-C₆ alkyl.Particular values include CH₂CH₂C(O)NHCH₂CH₂NMe₂ andCH₂C(O)NHCH₂CH₂NMe₂.

Examples of ¹³ when represented by(CH₂)_(n)(CR^(x)R^(y))C(O)NH—N═CHNR^(a)R^(b) include groups whereinR^(a) and R^(b) are independently H or C₁-C₆ alkyl. Particular valuesinclude CH₂C(CH₃)(OMe)C(O)NH—N═CHNMe₂.

Examples of R¹³ when represented by (C₁-C₆ alkyl)C(O)-heterocyclylinclude alkyl groups wherein any one of the hydrogens is replaced with aC(O)heterocyclyl moiety. In certain embodiments, the heterocyclyl is a5-6 membered ring having at least one nitrogen atom, for example apyrrolidinyl ring. Particular values include CH₂CH₂C(O)(pyrrolidin-1-yl)and CH₂C(O)(pyrrolidin-1-yl).

An example of R¹³ when represented by aryl is a phenyl group.

Examples of R¹³ when represented by heteroaryl include 5-6 memberedheteroaryl rings having one or two atoms independently selected from Nand S. Particular values include pyridyl and thienyl.

Examples of R¹³ when represented by (C₁-C₆ alkyl)hetAr¹ include alkylgroups wherein any one of the hydrogens is replaced with a hetAr¹ group.In certain embodiments, hetAr¹ is a 5-6 membered heteroaryl ring having2-4 atoms independently selected from N and O (provided the ring doesnot have an O—O bond). Examples include oxazolyl, oxadiazolyl andtetrazolyl rings. In certain embodiments, hetAr¹ is substituted withC₁-C₆ alkyl or OH. Particular values of R¹³ when represented by (C₁-C₆alkyl)hetAr¹ include the structures:

Examples of R¹³ when represented by CH₂(CR^(x)R^(y))C(O)OR⁸ includegroups wherein R⁸ is H or C₁-C₆ alkyl. Particular values includeCH₂C(CH₂)(OMe)CO₂Me and CH₂C(CH₂)(OMe)CO₂H.

Examples of R¹³ when represented by CH₂(CR^(x)R^(y))C(O)heterocyclylinclude groups wherein the heterocyclyl is a 5-membered heterocyclylhaving at least one nitrogen, for example pyrrolidinyl. In certainembodiments the heterocyclyl is substituted with O—(C₁-C₆ alkyl).Particular values include CH₂C(CH₂)(OMe)C(O)(pyrrolidin-1-yl) andCH₂C(CH₂)(OMe)C(O)-(3-methoxypyrrolidin-1-yl).

Examples of R¹³ when represented by CH₂CH(CO₂H)—CH₂CH₂NHR⁸ includegroups wherein R⁸ is H or C₁-C₆ alkyl. Particular values includeCH₂CH(CO₂H)—CH₂CH₂NH₂ and CH₂CH(CO₂H)—CH₂CH₂NHCO₂-(t-butyl).

Examples of R¹³ when represented by hetCyc¹ include groups whereinhetCyc¹ is a 5-6 membered ring having an atom selected from N and O.

An exemplary embodiment of hetCyc¹ is tetrahydrofuranyl:

Further exemplary embodiments of hetCyc¹ include piperidinyl andpyrrolidinyl.rings.

In certain embodiments, hetCyc¹ is C-linked, that is, hetCyc¹ is linkedto R¹ through a carbon atom of the hetCyc¹ ring.

In certain embodiments, hetCyc¹ is a piperidinyl or pyrrolidinyl.ringsubstituted by one or two groups independently selected from C₁-C₆alkyl, C(O)(C₁-C₆ alkyl), (C₁-C₆ alkyl)OH, C(O)O(C₁-C₆ alkyl),C(O)(C₁-C₆ alkyl)NR^(c)R^(d), C(O)(C₁-C₆ alkyl)OR^(c), C(O)CH₂C(O)(C₁-C₆alkyl), C(O)NR^(a)R^(b), SO₂NR^(c)R^(e), and SO₂R^(f).

For example, in certain embodiments, hetCyc¹ is a piperidinyl orpyrrolidinyl.ring optionally substituted with one or two groupsindependently selected from methyl, C(O)(C₁-C₆ alkyl), (C₁-C₆ alkyl)OH,C(O)O(C₁-C₆ alkyl), C(O)(C₁-C₆ alkyl)NH(C₁-C₈ alkyl), C(O)(C₁-C₆alkyl)NH(C₁-C₆ alkyl), C(O)(C₁-C₆ alkyl)NHCO₂ (C₁-C₆ alkyl), C(O)(C₁-C₆alkyl)OH, C(O)CH₂C(O)(C₁-C₆ alkyl), C(O)NH₂, C(O)NH(C₁-C₆ alkyl),C(O)N(C₁-C₆ alkyl)₂, SO₂NH₂, SO₂NMe₂, SO₂Me, SO₂ (C₂-C₆ alkyl)NH₂,C(═O)CHR^(g)NHC(═O)(C₁-C₆ alkyl); and C(═O)CH₂OC(═O)(C₁-C₆ alkyl).

In certain embodiments, the substituent is on the N atom of hetCyc¹.

Particular values for R¹³ when represented by hetCyc¹ include thestructures:

In particular embodiment of Formula I, hetCyc¹ has the formula

wherein A is C(═O)(C₁-C₆ alkyl), C(═O)NH₂, C(═O)NMe₁, CO₂Me, or SO₂NH₂,wherein any one of the carbons atoms of hetCyc¹ is optionallysubstituted with methyl. Particular values of hetCyc¹ include theformulas:

Examples of R¹³ when represented by CH₂ hetCyc² include groups whereinhetCyc² is a 5-6 membered ring having one or two nitrogen atoms.Examples include piperidinyl, pyrrolidinyl and piperazinyl groups. Incertain embodiments, hetCyc² is substituted with one or more groupsindependently selected from C₁-C₆ alkyl, C(O)(C₁-C₆ alkyl), C(O)O(C₁-C₆alkyl), and oxo. Particular values for R¹³ when represented by CH₂hetCyc² include the structures:

In certain embodiments, R¹² is H.

In certain embodiments of Formula I, R² includes, but are not limitedto, an aryl, or a saturated or partially unsaturated cycloalkyl ringselected from phenyl, 1-naphthyl, 2-naphthyl, 1-tetrahydronaphthalenyl,2-tetrahydronaphthalenyl, 3-tetrahydronaphthalenyl,4-tetrahydronaphthalenyl, 5-tetrahydronaphthalenyl,6-tetrahydronaphthalenyl, 7-tetrahydronaphthalenyl,8-tetrahydronaphthalenyl, cyclohexyl, cyclopentyl, cyclohexenyl, andsubstituted forms thereof.

In certain embodiments, R² is selected from

wherein R² is optionally substituted with one or more R^(20a) groups,wherein R^(20a) is selected from alkyl, alkenyl, alkynyl, saturated orpartially unsaturated cycloalkyl, saturated or partially unsaturatedheterocyclyl, aryl, heteroaryl, F, Cl, Br, I, CF₃, CN, OR⁶, C(═O)R⁶,C(═O)OR⁶, OC(═O)R⁶, C(═O)NR⁶R⁷, NR⁶R⁷, NR⁶C(═O)R⁷, SR⁶, S(O)R⁶, S(O)₂R⁶and SO₂NR⁶R⁷.

For example, in certain embodiments, R² is phenyl optionally substitutedwith one or more groups independently selected from F, Cl, Br, I, CN,alkyl, NO₂, SO₂R⁶, OR⁶, C(═O)OR⁶, and NR⁶C(═O)R⁷, wherein said alkyl isoptionally substituted with V_(n)—NR⁸R⁹, V_(n)—C(═O)OR⁸, orV_(n)—OC(═O)R⁸.

In other embodiments, R² is phenyl optionally substituted with one ormore groups independently selected from F, Cl, Br, CN, CF₃, C₁-C₆ alkyl,NO₂, —SO₂ (C₁-C₆ alkyl), OH, —O(C₁-C₆ alkyl), —CO₂H, —CO₂ (C₁-C₆ alkyl),—C(O)heterocyclyl [optionally substituted with C₁-C₆ alkyl],heterocyclyl and —C(O)NR⁸R⁹. In certain embodiments, R⁸ is H or C₁-C₆alkyl and R⁹ is H or C₁-C₆ alkyl optionally substituted with NH₂,NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl). Examples of the heterocycle group forthe C(O)heterocyclyl substituent of R² include 5-6 membered heterocyclicrings having one or two atoms selected from N and O (for examplemorpholinyl).

In particular embodiments of Formula I, R² is phenyl optionallysubstituted with one or two groups independently selected from F, Cl,Br, CN, CF₃, NO₂, SO₂Me, OMe, OH, CO₂H, CO₂Me, CO₂Et, C(O)NHCH₂CH₂NMe₂,C(O)NH₂, C(O)(4-methylpiperazinyl), and morpholinyl.

Exemplary embodiments of R² include, but are not limited to, thestructures:

Further exemplary embodiments of R₂ include the structures:

Exemplary embodiments of R² further include, but are not limited to,heteroaryl and saturated or partially unsaturated heterocyclic ringsselected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolinyl,3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl,8-quinolinyl, 2-quinoxalinyl, 3-quinoxalinyl, 5-quinoxalinyl,6-quinoxalinyl, 7-quinoxalinyl, 8-quinoxalinyl, benzo[d]thiazol-2-yl,4-benzo[d]thiazolyl, 5-benzo[d]thiazolyl, 6-benzo[d]thiazolyl,7-benzo[d]thiazolyl, 2-1H-benzo[d]imidazolyl, 1H-benzo[d]imidazole-4-yl,1H-benzo[d]imidazole-5-yl, 1H-benzo[d]imidazole-6-yl,1H-benzo[d]imidazole-7-yl, 2-thiophenyl, 3-thiophenyl,5-tetrahydroquinolinyl, 6-tetrahydroquinolinyl, 7-tetrahydroquinolinyl,8-tetrahydroquinolinyl, 5-tetrahydroisoquinolinyl,6-tetrahydroisoquinolinyl, 7-tetrahydroisoquinolinyl,8-tetrahydroisoquinolinyl, 1-pyrazolyl, 2-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,4-piperidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 4-pyrrolinyl, 5-pyrrolinyl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 5-piperidinyl,6-piperidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 4-pyrrolidinyl,5-pyrrolidinyl, and substituted forms thereof.

In other embodiments, R² is a 5-6 membered heteroaryl ring having 1-2nitrogen atoms. Examples of heteroaryl rings include 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidyl, 2-imidazolyl, and 4-imidazolyl. Incertain embodiments, R² is a heteroaryl ring optionally substituted withone or two groups independently selected from C₁-C₆ alkyl, CO₂ (C₁-C₆alkyl), C(O)NH(C₁-C₆ alkyl), C(O)NH(C₁-C₆ alkylN(di-C₁-C₆ alkyl), or(C₁-C₆ alkyl)OH.

In other embodiments, R² is a 9-10 membered bicyclic heteroaryl ringhaving a having 1 to 2 ring atoms independently selected from N and S.

In other embodiments, R² is a 5 membered heterocyclic ring having atleast one nitrogen atom, for example a pyrolidinyl ring. In certainembodiments, the heterocyclic ring is substituted with CO₂—(C₁-C₆alkyl), C(O)NH(C₁-C₆ alkyl), C(O)CH₂N(C₁-C₆ alkyl)₂, C(O)(C₁-C₆alkyl)CO₂H, or SO₂-(heteroaryl), wherein said heteroaryl of theSO₂-heteraryol group is a 5-membered ring having 1-2 nitrogen atoms andoptionally substituted with C₁-C₆ alkyl.

For example, in certain embodiments R² is selected from the structures:

-   -   and substituted forms thereof.

Further exemplary embodiments of R² when represented by a heteroarylring include the structures:

In certain embodiments of Formula I, Z is N.

In other embodiments of Formula I, Z is CR³.

In certain embodiment, R³ is selected from halogen, C(═O)R⁶, SR⁶, OR⁶,heteroaryl, alkyl, or alkenyl, wherein said heteroaryl, alkyl andalkenyl are optionally substituted.

In other embodiments, R³ is H, Br, Cl, SR⁶, OR⁶, aryl, heteroaryl, orC₁-C₆ alkyl, wherein said aryl is optionally substituted with Cl andsaid alkyl is optionally substituted with C(O)OR⁸, NR⁸R⁹, or OR⁸.

In certain embodiments, R³ includes Br, Cl and C(═O)H.

In certain embodiments, R³ is H.

In certain embodiments, R³ is Br.

In certain embodiments, R³ is SR⁶.

For example, in certain embodiments, R³ is SR⁶ wherein R⁶ is V_(n)-aryl,V_(n)-heteroaryl, V_(n)-heterocyclyl, V_(n)-cycloalkyl or alkyl, whereinsaid aryl, heteroaryl, heterocyclyl, cycloalkyl and alkyl portions areoptionally substituted. Exemplary embodiments include, but are notlimited to, the structures:

and substituted forms thereof.

In other embodiments, R³ is SR⁶ wherein R⁶ is V_(n)-aryl, n is 0, andaryl is phenyl optionally substituted with one or two groupsindependently selected from Cl, OH, CN, CF₃, CO₂H, —O(C₁-C₆ alkyl),—O(C₁-C₆ alkyl)CO₂H, —O(C₁-C₆ alkyl)NR^(a)R^(b), or —O(C₁-C₆alkyl)heterocycle wherein heterocycle is a 5-6 membered ring having anitrogen atom. In certain embodiments, R^(a) and R^(b) are independentlyH or C₁-C₆ alkyl.

Particular values of R³ when represented by S—(V_(n)-aryl) include—S-phenyl, —S-(2-chlorophenyl), —S-(3-chlorophenyl),—S-(4-methoxyphenyl), —S-(3-hydroxyphenyl), —S-(4-cyanophenyl),S-(4-carboxyphenyl), —S-(2-chloro-5-methoxyphenyl),—S-(3-methoxyphenyl), —S-(2,5-dimethoxyphenyl), —S-(2,5-dichlorophenyl),—S-(2,5-dimethylpyhenyl), —S-(2-hydroxyphenyl),—S-(2-trifluoromethyl-4-cyanophenyl),—S-(3-trifluoromethyl-4-cyanophenyl), —S-(4-cyanophenyl),

In other embodiments, R³ is SR⁶ wherein R⁶ is V_(n)-aryl, n is 1, V isalkyl optionally substituted with CH₂CH₂NR^(a)R^(b), and aryl is phenyloptionally substituted with F, Cl, or O(C₁-C₆ alkyl). In certainembodiments R^(a) and Rb are independently H or alkyl.

Particular values of R³ when represented by S—(V_(n)-aryl) furtherinclude S—CH₂-Ph, S—CH₂-(3-methoxyphenyl), S—CH₂-(4-methoxyphenyl),S—CH₂-(3-chlorophenyl), S—CH₂-(2-fluorophenyl), and

In other embodiments, R³ is SR⁶ wherein R⁶ is V_(n)-heteroaryl, n is 1and V is C₁-C₆ alkyl. In certain embodiments, V is substituted withC₁-C₆ alkyl. Examples of heteroaryl groups include 5-6 membered ringshaving 1-2 atoms independently selected from N, S and O (provided thering does not contain an O—O bond). Particular examples of heteroarylgroups include pyridyl, thiazolyl, thiadiazolyl, oxadiazolyl, andoxazolyl rings. In certain embodiments, the heteroaryl ring issubstituted with one or two groups independently selected from Cl, OH,—O(C₁-C₆ alkyl), C₁-C₆ alkyl, (3-6C)cycloalkyl and —NHC(O)(C₁-C₆ alkyl).Particular values for R³ when represented by S—V_(n)-heteroaryl include

In other embodiments, R³ is SR⁶ wherein R⁶ is V_(n)-heteroaryl, n is 1,V is C₁-C₆ alkyl, and heteroaryl is a 10-membered bicyclic heteroarylhaving at least one nitrogen, such as quinolinyl. A particular value ofR³ when represented by S—V_(n)-heteroaryl is:

In certain embodiments, R³ is —SR⁶ wherein R⁶ is V_(n)-heteroaryl, n is0, and the heteroaryl group is a 5-6 membered ring having 1-4 atomsindependently selected from N and S. Examples include pyridyl,pyrimidyl, thiazolyl, tetrazolyl, and triazolyl rings. In certainembodiments, the heteroaryl ring is substituted with one or two groupsindependently selected from Cl, CN, C₁-C₆ alkyl, —O(C₁-C₆ alkyl),—(C₁-C₆ alkyl)NR^(a)R^(b), —(C₁-C₆ alkyl)CN, C(═O)O(C₁-C₆ alkyl), andCF₃. In certain embodiments, R^(a) and R^(b) are independently H orC₁-C₆ alkyl.

Particular values for R³ when represented by —S-heteroaryl include—S-(2-pyridyl), —S-(3-pyridyl), —S-(4-pyridyl), —S-(2-pyrimidyl),—S-(6-methylpyrid-2-yl), —S-(2-chloropyrid-4-yl),—S-(2-chloropyrimind-4-yl), —S-(4,6-dimethylpyrimid-2-yl),—S-(4-methoxypyrimid-2-yl), —S-(2-methoxymethylpyrimid-4-yl),—S-(4-methylthiazol-2-yl),—S-(1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl),—S-(4-methyl-4H-1,2,4-triazol-3-yl),—S-(5-cyanomethyl-4H-1,2,4-triazol-3-yl), —S-(5-cyanopyrid-2-yl),—S-(2-cyano-3-methoxypyrid-5-yl), —S-(2-trifluoromethylpyrid-5-yl), and—S-(2-ethoxycarbonylpyrid-6-yl).

In certain embodiments, R³ is represented by —S—CHR^(6a)R^(6b). Incertain embodiments, R^(6b) is pyridyl or pyrimidyl and R^(6a) ispiperidyl or a group having the formula,

wherein R^(6a) is optionally substituted with C₁-C₆ alkyl, C(O)O(C₁-C₆alkyl), or C₁-C₆ alkyl)OH. Particular values for R³ when represented byS—CHR^(6a)R^(6b) include:

In other embodiments, R³ is represented by S—CHR^(6a)R^(6b) whereinR^(6a) is a piperidyl ring optionally substituted with C₁-C₆ alkyl, andR^(6b) is C(O)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)OH, C(O)NH(C₁-C₆ alkyl) orC(O)NH-heterocycle. Examples of heterocycle groups include 5-6 memberedrings having at least one nitrogen atom (e.g., pyrrolidinyl orpiperidinyl), a 10-membered partially unsaturated bicyclic ring havingat least one nitrogen atom (e.g., tetrahydroquinolinyl), and a7-membered bridged heterocyclic ring having at least one nitrogen atom(e.g., 7-azabicyclo[2.2.1]heptyl). In certain embodiments theheterocyclic ring is substituted with C₁-C₆ alkyl. Particular values forR³ when represented by S—CHR^(6a)R^(6b) further include:

In other embodiments, R³ is represented by S—CHR^(6a)R^(6b) whereinR^(6a) is piperidyl optionally substituted with (C₁-C₆ alkyl)OH, andR^(6b) is heteroaryl. Examples of heteroaryl groups include 5 memberedrings having 1-3 atoms selected from N and O (provided the ring does notcontain an O—O bond), for example oxadiazolyl. In certain embodiments,the heteroaryl ring is substituted with C₁-C₆ alkyl. A particular valueof R³ when represented by S—CHR^(6a)R^(6b) further includes:

In other embodiments, R³ is represented by S—CHR^(6a)R^(6b) whereinR^(6a) is piperidyl and R^(6b) is H or C₁-C₆ alkyl. Particular examplesinclude:

In certain embodiments, R³ is SR⁶ wherein R⁶ is V_(n)-heteroaryl, n is0, and the heteroaryl group is a 9-10 membered bicyclic heteroaromaticring having 2-3 atoms independently selected from N, S and O (providedthe ring does not contain O—O bonds). Examples include 5-6-memberedheteroaryl rings fused to 5-6 membered heteroaryl, heterocyclyl, orcycloalkyl rings. Particular examples include thienopyridyl,thienopyrimidyl, isoxazolopyridyl, cyclopentapyridyl, pyrazolopyrimidyl,furopyridyl, tetrahydropyridopyrimidyl, and triazolopyridyl rings. Incertain embodiments, the heteroaryl ring is substituted with one or twogroups independently selected from I, Br, C₁-C₆ alkyl and CO₂H.

Particular values of R³ when represented by S-heteroaryl include:

In certain embodiments, R³ is SR⁶ wherein R⁶ is heterocycle. Examples ofheterocycles include 6 membered rings having at least one nitrogen atom(e.g., piperidinyl). In certain embodiments, the heterocycle issubstituted with oxo. A particular value of R³ is

In certain embodiments, R³ is SR⁶ wherein R⁶ is (C₁-C₆ alkyl)C(O)OR⁸.Examples include alkyl groups wherein any one of the hydrogens isreplaced with a C(O)OR⁸ moiety. In certain embodiments, R⁸ is C₁-C₆alkyl. A particular value of R³ is S—CH₂CH₂C(O)OCH₃.

In certain embodiments, R³ is SR⁶ wherein R⁶ is CH₂C(O)-heterocycle,CH₂C(O)—NR⁸ (C₁-C₆ alkyl)NR^(a)R^(b), CH₂C(O)—NR⁸ (C₁-C₆alkyl)heterocycle, or (C₁-C₆ alkyl)NR⁸R⁹. In certain embodiments, eachR⁸, R⁹, R^(a) and R^(b) is independently selected from H and (C₁-C₆alkyl). Examples of heterocycle groups include 5-6 membered rings having1-2 nitrogen atoms, wherein the ring is optionally substituted with(C₁-C₆ alkyl). Particular values for R³ include

In certain embodiments, R³ is OR⁶ wherein R⁶ is H, alkyl, V_(n)-aryl, orV_(n)-heteroaryl, wherein said alkyl, V_(n)-aryl, and V_(n)-heteroarylare optionally substituted.

In other embodiments, R³ is OR⁶ wherein R⁶ is H, C₁-C₆ alkyl, (C₁-C₆alkyl)aryl, (C₁-C₆ alkyl)heterocycle, (C₁-C₆ alkyl)NR⁸R⁹, or phenyloptionally substituted with Br. In certain embodiments, R⁸ and R⁹ areindependently H or (C₁-C₆ alkyl). Examples of heterocycles include 5-6membered rings having at least one nitrogen atom, for example piperidyl.

Exemplary embodiments of OR⁶ include, but are not limited to, OH, OMe,

Further exemplary embodiments of R³ when represented by OR⁶ includephenoxy and 3-bromophenoxy.

In certain embodiments R³ is optionally substituted aryl or heteroaryl.

Examples of R³ when represented by an aryl group include phenyloptionally substituted with a halogen, for example chloro. A particularexample is 2-chlorophenyl.

Examples of R³ when represented by a heteroaryl group include 6 memberedrings having at least one nitrogen atom.

Exemplary embodiments include, but are not limited to, the structures:

and substituted forms thereof.

In certain embodiments R³ is optionally substituted alkyl or alkenyl.

In certain embodiments, R³ is C₁-C₆ alkyl, (C₁-C₁alkyl)heterocycle,(C₁-C₁ alkyl)heteroaryl, (C₁-C₁ alkyl)OH, (C₁-C₁ alkyl)CO₂R⁸, (C₁-C₁alkyl)CO₂ (C₁-C₁ alkyl), (C₁-C₁ alkyl)NR⁸R⁹, or (C₂-C₆ alkenyl)CO₂R⁸,wherein R⁸ and R⁹ are independently H or C₁-C₆ alkyl. Examples ofheterocyclic rings include 5-6 membered rings having one or two atomsindependently selected from N and O. Examples of heteroaryl ringsinclude 5-6 membered rings having at least one nitrogen atom.

Exemplary embodiments of R³ include, but are not limited to, thestructures:

and substituted forms thereof.

Additional examples of R³ include CH₂OH, CH₂-(tetrahydro-2H-pyran-4-yl),4-dimethylaminobuten-1-yl, and 4-dimethylaminobutyl.

The compounds of Formula I include compounds having the Formula Ib

and salts thereof, wherein:

R³ is

A is C(═O)(C₁-C₆ alkyl), C(═O)NH₂, C(═O)NMe₂, SO₂Me, or SO₂NH₂

L is O or S;

Y is CH;

D² is N or CR¹²;

R² is aryl or heteroaryl, wherein said aryl and heteroaryl areoptionally substituted with one or more groups independently selectedfrom C₁-C₆ alkyl, F, Cl, Br, CF₃, CN, OR⁶, C(═O)R⁶, C(═O)OR⁶,C(═O)NR⁶R⁷, S(O)₂R⁶, and C(O)CH₂NH₂;

R³ is SR⁶ or OR⁶;

R⁶ is V_(n)-aryl or V_(n)-heteroaryl, wherein said aryl and heteroarylportions are optionally substituted with one or more groupsindependently selected from C₁-C₆ alkyl, saturated and partiallyunsaturated C₁-C₆ heterocyclyl [optionally substituted with C(O)O(C₁-C₆alkyl) or (C₁-C₆ alkyl)OH], aryl, heteroaryl, F, Cl, Br, I, CN, OR⁸,C(═O)R⁸, C(═O)OR^(S), C(═O)NR⁸R⁹, NR⁸R⁹, NR⁸C(═O)R⁹ or (C₁-C₆ alkyl)OH;

R⁷ is H or C₁-C₁₂ alkyl;

R¹¹ is H;

R¹² is H or C₁-C₆ alkyl;

V is alkylene having from 1 to 4 carbons, wherein said alkylene isoptionally substituted with C₁-C₆ alkyl, O(C₁-C₆ alkyl), or (C₁-C₆alkyl)NR^(c)R^(e);

each R^(c) and R^(e) is independently H or C₁-C₆ alkyl; and

n is 0 or 1.

The compounds of Formula I include compounds having the Formula Ic

and salts thereof, wherein:

R¹³ is

A is C(═O)(C₁-C₆ alkyl), C(═O)NH₂, C(C═O)NH(C₁-C₆ alkyl), C(═O)N(C₁-C₆alkyl)₂, C(═O)CH(C₁-C₆ alkyl)N(C₁-C₆ alkyl)₂, SO₂ (C₁-C₆ alkyl), SO₂NH₂,SO₂NH(C₁-C₆ alkyl), S(C₁-C₆ alkyl)₂ or C(O)CH(CH₃)OH;

L is O;

D² is N or CH;

R² is aryl optionally substituted with one or more groups independentlyselected from C₁-C₆ alkyl, F, Br, and CF₃;

R³ is SR⁶;

R⁶ is aryl, hetAr^(a) or hetAr^(b), wherein R⁶ is optionally substitutedwith one or more groups independently selected from C₁-C₆ alkyl, Br, C₁,CF₃, CN, OR⁸, and C(═O)OR⁸;

R⁸ is C₁-C₆ alkyl;

hetAr^(a) is a 5-6 membered heteroaryl ring having 1-4 nitrogen atoms;and

hetAr^(b) is a 9-10 membered bicyclic heteroaromatic ring having 2-6atoms independently selected from N, S and O (provided the ring does notcontain an O—O bond).

In one embodiment, A is selected from C(═O)(C₁-C₆ alkyl), C(═O)NH₂,C(═O)NMe₂, C(═O)CH₂NMe₂, SO₂Me, SO₂NH₂, and C(O)CH(CH₃)OH.

In certain embodiments of Formula Ic, A is C(═O)(C₁-C₆ alkyl).

In certain embodiments of Formula Ic, A is C(═O)NH₂.

In certain embodiments of Formula Ic, A is C(═O)NMe₂.

In certain embodiments of Formula Ic, A is C(═O)CH₂NMe₂.

In certain embodiments of Formula Ic, A is SO₂Me.

In certain embodiments of Formula Ic, A is SO₂NH₂.

In certain embodiments of Formula Ic, A is C(O)CH(CH₃)OH.

In certain embodiments, R² is aryl optionally substituted with one ormore groups independently selected from C₁-C₆ alkyl, Br, C₁, CF₃, CN,OR⁸, and C(═O)OR⁸. In certain embodiments, R² is phenyl. Particularvalues for R² include phenyl optionally substituted with one or twogroups independently selected from F, Br and CF₃.

Exemplary embodiments of R² for Formula Ic include, but are not limitedto, the structures:

In certain embodiments of Formula Ic, R³ is SR⁶ wherein R⁶ is aryl. Inparticular embodiment, the aryl group is phenyl. In certain embodiments,the aryl group is substituted with one or two groups independentlyselected from CN, CF₃, and —O(C₁-C₆ alkyl). Particular values of R³ whenrepresented by S-aryl include the structures:

In certain embodiments of Formula Ic, R³ is SR⁶ wherein R⁶ is hetAr^(a),and hetAr^(a) is a 5-6 membered heteroaryl ring having 1-4 nitrogenatoms. In particular examples, hetAr^(a) is a 5-6 membered ring having1-2 nitrogen atoms. Examples include pyridyl and pyrimidyl rings. Incertain embodiments, hetAr^(a) is substituted with one or two groupsindependently selected from Cl, CN, —O(C₁-C₆ alkyl), C(═O)O(C₁-C₆alkyl), and CF₃. Particular values for R³ for Formula Ie whenrepresented by S-hetAr^(a) include the structure:

In certain embodiments of Formula I, R³ is SR⁶ wherein R⁶ is hetAr^(b)and hetAr^(b) is a 9-10 membered bicyclic heteroaromatic ring having 2-6heteroatoms independently selected from N, S and O (provided the ringdoes not contain an O—O bond). In particular embodiments, hetAr^(b) is a9-10 membered bicyclic heteroaromatic ring having 2-3 heteroatomsindependently selected from N, S and O. Examples include 5-6-memberedheteroaryl rings fused to 5-6 membered heteroaryl rings. Particularexamples include thienopyridyl, thienopyrimidyl, isoxazolopyridyl,pyrazolopyrimidyl and rings. In certain embodiments, hetAr^(b) issubstituted with one or two groups independently selected from Br, C₁and C₁-C₆ alkyl.

Particular values of R³ for Formula Ic when represented by S— hetArbinclude the structures:

The compound of Formula I also include compound of Formula Id:

and salts thereof, wherein:

R¹³ is

A is C(═O)(C₁-C₆ alkyl), C(═O)NH₂, C(═O)NMe₂, C(═O)CH₂NMe₂, SO₂Me, orSO₂NH₂;

D² is N or CH;

R² is phenyl optionally substituted with F; and .

R³ is selected from and N

Exemplary embodiments of compounds of Formula I include, but are notlimited to,

and substituted forms thereof, wherein L, R¹, R², R³, R⁴ and R¹¹ are asdefined herein.

Additional exemplary embodiment of compounds of Formula I include, butare not limited to, compounds of the general formulas

and substituted forms thereof, wherein L, R², R³, R⁴, R¹¹, R¹² and R¹³are as defined herein.

Additional exemplary embodiment of compounds of Formula I include, butare not limited to, compounds of the general formulas

and substituted forms thereof, wherein L, R¹, R³, R⁴, and R¹¹ are asdefined herein.

Additional exemplary embodiment of compounds of Formula I include, butare not limited to, compounds of the general formulas

and substituted forms thereof, wherein R¹, R³, R⁴, and R¹¹ are asdefined herein.

Additional exemplary embodiment of compounds of Formula I include, butare not limited to, compounds of the general formulas

and substituted forms thereof, wherein R¹, R³, R⁴, R¹¹, R¹² and R¹³ areas defined herein. In certain embodiments, the phenyl ring is optionallysubstituted with one or more R^(20a) groups independently selected fromF, Cl, Br, I, CN, C₁-C₁₂ alkyl, NO₂, SO₂R⁶, OR⁶, C(═O)OR⁶, andNR⁶C(═O)R⁷, wherein said alkyl is optionally substituted. In certainembodiments, the phenyl group is optionally substituted with one or moregroups independently selected from Cl, OMe, CN, NO₂, C(═O)OMe, C(═O)OEt,SO₂Me, and OCH₂CH₂NMe₂. In certain embodiments, R¹² is H and R¹³ isselected from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, and (CH₂)₁₋₂ CO₂R⁶. Incertain embodiments, R¹³ is methyl, ethyl, propyl, isopropyl, n-butyl,isobutyl, cyclopropyl, CH₂CH₂COOMe, CH₂COOEt, CH₂COOH, or CH₂CH₂COOH.

Additional exemplary embodiment of compounds of Formula I include, butare not limited to, compounds of the general formulas

wherein R⁴, R⁶, R¹¹, R¹², R¹³, and R^(20a) are as defined herein.

Additional exemplary embodiment of compounds of Formula I include, butare not limited to, compounds of the general formulas

and substituted forms thereof, wherein L, R¹, R⁴, and R¹¹ are as definedherein.

Additional exemplary embodiment of compounds of Formula I include, butare not limited to, compounds of the general formulas

and substituted forms thereof, wherein L, R¹, R³, and R⁴ are as definedherein.

Additional exemplary embodiment of compounds of Formula I include, butare not limited to, compounds of the general formulas

and substituted forms thereof, wherein L, R¹, R³, and R¹¹ are as definedherein.

Additional exemplary embodiment of compounds of Formula I include, butare not limited to, compounds of the general formulas

and substituted forms thereof, wherein L, R³, R⁴, R¹¹, R¹² and R¹³ areas defined herein.

Additional exemplary embodiment of compounds of Formula I include, butare not limited to, compounds of the general formulas

and substituted forms thereof, wherein L, R³, R⁴, R¹¹ and R²⁰ are asdefined herein, and each R²⁰ is independent of the other.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers anddiastereomers, and mixtures, racemic or otherwise, thereof. Accordingly,this invention also includes all such isomers, including diasteremericmixtures, pure diastereomers and pure enantiomers of the compounds ofthis invention. The term “enantiomer” refers to two stereoisomers of acompound which are non-superimposable mirror images of one another. Theterm “diastereomer” refers to a pair of optical isomers which are notmirror images of one another. Diastereomers have different physicalproperties, e.g. melting points, boiling points, spectral properties,and reactivities.

The compounds of the present invention may also exist in differenttautomeric forms, and all such forms are embraced within the scope ofthe invention. The term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible by alow energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions by migration of aproton, such as keto-enol and imine-enamine isomerizations. Valencetautomers include interconversions by reorganization of some of thebonding electrons.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

In addition to compounds of Formula I, the invention also includessolvates, pharmaceutically acceptable prodrugs, and salts of suchcompounds.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the invention. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.The term “hydrate” can also be used to refer to a complex wherein thesolvent molecule is water.

A “prodrug” is a compound that may be converted under physiologicalconditions or by solvolysis to the specified compound or to a salt ofsuch compound. Prodrugs include compounds wherein an amino acid residue,or a polypeptide chain of two or more amino acid residues, is covalentlyjoined through an amide or ester bond to a free amino, hydroxy orcarboxylic acid group of a compound of the present invention. The aminoacid residues include but are not limited to the 20 naturally occurringamino acids commonly designated by three letter symbols and alsoincludes phosphoserine, phosphothreonine, phosphotyrosine,4-hydroxyproline, hydroxylysine, demosine, isodemosine,gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylicacid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, cirtulline, homocysteine, homoserine,methyl-alanine, para-benzoylphenylalanine, phenylglycine,propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.

Additional types of prodrugs are also encompassed. For instance, a freecarboxyl group of a compound of Formula I can be derivatized as an amideor alkyl ester. As another example, compounds of this inventioncomprising free hydroxy groups may be derivatized as prodrugs byconverting the hydroxy group into a group such as, but not limited to, aphosphate ester, hemisuccinate, dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl group, as outlined in Advanced DrugDelivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and aminogroups are also included, as are carbonate prodrugs, sulfonate estersand sulfate esters of hydroxy groups. Derivatization of hydroxy groupsas (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group maybe an alkyl ester optionally substituted with groups including, but notlimited to, ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem., 1996,39, 10. More specific examples include replacement of the hydrogen atomof the alcohol group with a group such as (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl,(C₁-C₆)alkoxycarbonyloxymethyl, N—(C₁-C₆)alkoxycarbonylaminomethyl,succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkanoyl, arylacyl andα-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group isindependently selected from the naturally occurring L-amino acids,P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting fromthe removal of a hydroxyl group of the hemiacetal form of acarbohydrate).

Free amines of compounds of Formula I can also be derivatized as amides,sulfonamides or phosphonamides. All of these moieties may incorporategroups including, but not limited to, ether, amine and carboxylic acidfunctionalities. For example, a prodrug can be formed by the replacementof a hydrogen atom in the amine group with a group such as R-carbonyl,RO-carbonyl, NRR′-carbonyl, wherein R and R′ are each independently(C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, or benzyl, or R-carbonyl is a naturalα-aminoacyl or natural α-aminoacyl-natural α-aminoacyl, —C(OH)C(O)OYwherein Y is H, (C₁-C₆)alkyl or benzyl, —C(OY₀)Y₁ wherein Y₀ is (C₁-C₄)alkyl and Y₁ is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl ormono-N— or di-N,N—(C₁-C₆)alkylaminoalkyl, or —C(Y₂)Y₃ wherein Y₂ is H ormethyl and Y₃ is mono-N— or di-N,N—(C₁-C₆)alkylamino, morpholino,piperidin-1-yl or pyrrolidin-1-yl.

For additional examples of prodrug derivatives, see, for example, a)Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methodsin Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985); b) A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design andApplication of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H.Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988);and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each ofwhich is specifically incorporated herein by reference.

A compound of the invention may possess a sufficiently acidic group, asufficiently basic group, or both functional groups, and accordinglyreact with any of a number of inorganic or organic bases or acids toform a salt. Examples of salts include those salts prepared by reactionof the compounds of the present invention with a mineral or organic acidor an inorganic base, such salts including, but not limited to,sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyn-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates,methanesulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates. Since a single compound of thepresent invention may include more than one acidic or basic moiety, thecompounds of the present invention may include mono, di or tri-salts ina single compound.

If the inventive compound is a base, the desired salt may be prepared byany suitable method available in the art, for example, by treatment ofthe free base with an acidic compound, for example an inorganic acidsuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, or with an organic acid, such as aceticacid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonicacid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, apyranosidyl acid such as glucuronic acid or galacturonic acid, an alphahydroxy acid such as citric acid or tartaric acid, an amino acid such asaspartic acid or glutamic acid, an aromatic acid such as benzoic acid orcinnamic acid, a sulfonic acid such as p-toluenesulfonic acid orethanesulfonic acid, or the like.

If the inventive compound is an acid, the desired salt may be preparedby any suitable method, for example, by treatment of the free acid withan inorganic or organic base. Examples of suitable inorganic saltsinclude those formed with alkali and alkaline earth metals such aslithium, sodium, potassium, barium and calcium. Examples of suitableorganic base salts include, for example, ammonium, dibenzylammonium,benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium,phenylethylbenzylamine, dibenzylethylenediamine, and the like salts.Other salts of acidic moieties may include, for example, those saltsformed with procaine, quinine and N-methylglucosamine, plus salts formedwith basic amino acids such as glycine, ornithine, histidine,phenylglycine, lysine and arginine.

In certain embodiments, the salt of a compound of Formula I is apharmaceutically acceptable salt. The phrase “pharmaceuticallyacceptable” indicates that the substance or composition is compatiblechemically and/or toxicologically with the other ingredients comprisinga formulation, and/or the mammal being treated therewith. A“pharmaceutically acceptable salt,” unless otherwise indicated, includessalts that retain the biological effectiveness of the corresponding freeacid or base of the specified compound and are not biologically orotherwise undesirable.

The present invention also embraces isotopically-labeled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature.

Metabolites of Compounds of Formula I

Also falling within the scope of this invention are the in vivometabolic products of compounds of Formula I described herein. A“metabolite” is a pharmacologically active product produced throughmetabolism in the body of a specified compound or salt thereof. Suchproducts may result, for example, from the oxidation, reduction,hydrolysis, amidation, deamidation, esterification, deesterification,enzymatic cleavage, and the like, of the administered compound.Accordingly, the invention includes metabolites of compounds of FormulaI, including compounds produced by a process comprising contacting acompound of this invention with a mammal for a period of time sufficientto yield a metabolic product thereof.

Synthesis of Gluocokinase Activators

Compounds of this invention may be synthesized by synthetic routes thatinclude processes analogous to those well known in the chemical arts,particularly in light of the description contained herein. The startingmaterials are generally available from commercial sources such asAldrich Chemicals (Milwaukee, Wis.) or are readily prepared usingmethods well known to those skilled in the art (e.g., prepared bymethods generally described in Louis F. Fieser and Mary Fieser, Reagentsfor Organic Synthesis, v. 1-19, Wiley, N.Y. (1967-1999 ed.), orBeilsteins Handbuch der organischen Chemie, 4, Aufl. ed.Springer-Verlag, Berlin, including supplements).

Compounds of Formula I may be prepared singly or as compound librariescomprising at least 2, for example 5 to 1,000 compounds, or 10 to 100compounds. Libraries of compounds of Formula I may be prepared by acombinatorial ‘split and mix’ approach or by multiple parallel synthesesusing either solution phase or solid phase chemistry, by proceduresknown to those skilled in the art. Thus according to a further aspect ofthe invention there is provided a compound library comprising at least 2compounds of Formula I or salts thereof.

For illustrative purposes, Schemes A-U show general methods forpreparing the compounds of the present invention as well as keyintermediates. For a more detailed description of the individualreaction steps, see the Examples section below. Those skilled in the artwill appreciate that other synthetic routes may be used to synthesizethe inventive compounds. Although specific starting materials andreagents are depicted in the Schemes and discussed below, other startingmaterials and reagents can be easily substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of thecompounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

Scheme A shows a method of preparing compounds (3A) of Formula I whereinR¹ is thiazolyl and L=O or S. To prepare compound (3A), a2-aminoheterocycle (1) is reacted with benzoylisothiocyanate to afford abenzoylthiourea intermediate, which is hydrolyzed to the thiourea (2)with a base such as, but not limited to, potassium carbonate in asuitable solvent such as, but not limited to, ethanol. Alternatively,the aminoheterocycle (1) can be treated with an inorganic or ammoniumisothiocyanate, e.g., Meckler's procedure, in the presence of an acid toafford the thiourea (2) in one step. Treatment of the thiourea (2) withan α-haloketone R¹³COCHR¹²X, wherein X=OTs, Cl, Br, I, or NR₃ (whereinR═C₁-C₆ alkyl), in a suitable base such as triethylamine, Hunig's base,DBU, alkali carbonate, sodium hydroxide, etc. and a suitable solventsuch as ethanol affords the thiazole (3A). If the desired α-halo ketoneR¹³COCHR¹²X is not commercially available, it can be prepared by variousmethods known to those skilled in the art. Examples include, but are notlimited to, bromination of commercially or readily synthesized methylketones (Tetrahedron (1970) 5611-5615; Organic Synthesis (1946) 13-15;Tetrahedron (1990) 2943-2964), diazomethane treatment of carbonylchlorides, oxidation of 1-chloro-2-alkanols, bromination of silyl enolethers, or halogenation of β-keto esters followed by decarboxylation.

Scheme B shows an alternative method of preparing a compound of FormulaI. According to Scheme B, hydroxylated heteroaryl halide (5) (if notcommercially available) can be prepared from heteroaryl halide (4)by: 1) ortho metalation with LDA or another suitable base; 2) conversionof the anion to the boronate by reaction with B(OR)₃; and 3) oxidationof the boronate with a suitable oxidant such as N-methylmorpholine oxideor hydrogen peroxide. The ortho metalated species can also be quenchedwith (TMSO)₂ to obtain the hydroxylated material (5) directly uponacidic workup. The hydroxylated heteroaromatic compound (5) can bealkylated with R²X in the presence of a base such as, but not limitedto, cesium carbonate or sodium hydride and in a suitable solvent suchas, but not limited to, DMF to afford compound (6) wherein L is O.Examples of R²X that may be utilized include substituted 2- and4-nitrohalobenzenes, substituted 2- and 4-cyanohalobenzenes,2-chloro-1-fluorobenzene, halogenated pyridines, halogenatedpyrimidines, and other halogenated heterocycles. Compound (6) can beconverted to compound (7) by the method of Hartwig et al. (for anexample of this transformation by analogy see: Organic Letters (2001)2729-2732), or by treatment with a Pd catalyst and benzophenone imine,or by heating in the presence of ammonia (or NH₂PG where PG is aprotecting group).

Compounds of the formulas (6) and (7) wherein L is S can be preparedaccording to methods described in Schemes I, J, K, M, N, O, and P.Compounds of the formulas (6) and (7) wherein L is CH₂ can be preparedaccording to methods described below in Schemes I, K, M, N, O, and P.Compounds of formulas (6) and (7) subsequently can be used in SchemesA-H.

Compound (7) can be converted to compound (3) of Formula I upon reactionwith an aryl or heteroaryl halide R¹X in the presence of a base catalystor metal (e.g., copper or palladium) catalyst. Alternatively, compound(6) can be converted directly to a compound (3) of Formula I upontreatment with R¹NH₂ by base catalysis or by copper or palladiumcatalysis; i.e., the Buchwald reaction.

Scheme C shows a method of preparing 2-aminothiazole and 2-bromothiazoleintermediates (8) and (9), respectively, which are suitable for use inpreparing compounds of Formula I as shown in Scheme B. According toScheme C, α-haloketone R¹³COCHR¹²X can be treated with thiourea in thepresence of a suitable base such as potassium carbonate or triethylaminein an appropriate solvent such as DMF or ethanol to afford aminothiazole(8). The aminothiazole (8) can be converted to a diazonium saltintermediate by numerous methods including, but not limited to,treatment with sodium nitrite in acid or isobutylnitrite. Treatment ofthe in situ diazonium salt with Cu(X¹)₂ (X¹═Cl or Br) or HBr affords thecorresponding 2-halothiazole (9). Alternatively, using the Hantzschsynthetic method, the α-haloketone R¹³COCHR¹²X can be treated first withKSCN, then with HX wherein X is Cl or Br, to provide the 2-halothiazole(9). The 2-halothiazole compounds (8) and (9) can be converted intocompound (3A) by the methods shown in Scheme B.

Scheme D shows a method of preparing 3-aminothiadiazole and3-bromothiadiazole intermediates (11) and (12), respectively, which aresuitable for use in preparing compounds of Formula I as shown in SchemeB. According to Scheme D, acylguanidine (10) (Can. J. Chem., (1961) 39,1017-29) can be treated with Lawesson's reagent or similar reagent in anappropriate solvent such as toluene to afford the correspondingthioamide (EP 0307142). Oxidation of the thioamide to form 3-amino-1,2,4thiadiazole (11) can be accomplished with bromine, iodine, hydrogenperoxide or nitric acid. Cyclization of compound (10) may also beachieved by treatment with hydroxylamine-O-sulphonic acid in an alcoholsolvent such as methanol or ethanol in the presence of pyridine (EP0307142). Formation of the diazonium salt of compound (11), followed bytreatment of the in situ diazonium salt with CuBr₂, affords thecorresponding 3-bromo-1,2,4-thiadiazole (12) (EP 0307142). The chloroderivative of compound (12) could also be synthesized through the use ofCuCl₂. Alternatively, palladium-mediated coupling of the commerciallyavailable 3-bromo-5-chloro-1,2,4-thiadiazole (13) with a zinc reagentaffords 3-bromo-1,2,4-thiadiazole (12) (WO 2003/037894). Intermediatethiadiazoles (11) and (12) can be converted into compound (3B) ofFormula I by the methods shown in Scheme B.

Scheme E shows a method of preparing 5-amino-1,2,4-thiadiazole and5-chloro-1,2,4-thiadiazole intermediates (15) and (16), respectively,which are suitable for use in preparing compounds of Formula I as shownin Scheme B. According to Scheme E, primary amide (14) can be convertedinto 5-amino-1,2,4 thiadiazole (15) by heating with KSCN in anappropriate solvent such as methanol or ethanol (Adv. Heterocycl. Chem.,(1982) 32, 285). Formation of the diazonium salt of compound (15),followed by treatment of the in situ diazonium salt with CuCl₂ affordsthe corresponding 5-chloro-1,2,4-thiadiazole (16). The correspondingbromo derivative can also be synthesized through the use of CuBr₂.Alternatively, reaction of amidine (17) with perchloromethyl mercaptanaffords 5-chloro-1,2,4-thiadiazole (16) (Bioorg. Med. Chem., (2003) 11,5529-5537). Intermediates (15) and (16) can be converted into compound(3C) of Formula I by the methods shown in Scheme B.

Scheme F shows a method of preparing 3-amino-1,2,4-oxadiazole and3-bromo-1,2,4-oxadiazole intermediates (19) and (20), respectively,which are suitable for use in preparing compounds of Formula I as shownin Scheme B. According to Scheme F, cyanamide can be reacted with anappropriate acylchloride (18) or the corresponding anhydride, andsubsequently reacted with hydroxylamine to afford3-amino-1,2,4-oxadiazole (19) (Heterocycles, (2002) 57, 811-823).Formation of the diazonium salt of (19), followed by treatment of the insitu diazonium salt with CuBr₂ affords the corresponding3-bromo-1,2,4-oxadiazole (20). The chloro derivative could also besynthesized through the use of CuCl₂. Alternatively, alkyl nitrile (21)can be reacted with dibromoformaldoxime (neat) in the presence of anappropriate base such as sodium bicarbonate to afford3-bromo-1,2,4-oxadiazole (20) (J. Heterocyclic Chem., (1989) 26, 23-24).The oxadiazole intermediates (19) and (20) can be converted intocompound (3D) of Formula I by the methods shown in Scheme B.

Scheme G shows a method of preparing 5-amino-1,2,4-oxadiazole and5-chloro-1,2,4-oxadiazole intermediates (23) and (24), respectively,which are suitable for use in preparing compounds of Formula I as shownin Scheme B. According to Scheme G, imidate hydrochloride salt (22)(made by the Pinner reaction) can be reacted with cyanamide in asuitable solvent such as methanol or ethanol to afford an intermediateN-cyanoimidate. Cyclization can be achieved by reacting theN-cyanoimidate with hydroxylamine hydrochloride in an appropriatesolvent such as methanol or ethanol in the presence of an appropriatebase such as triethylamine, Hunig's base, pyridine or sodium acetate toafford 5-amino-1,2,4-oxadiazole (23) (J. Org. Chem., (1963) 28,1861-21). Formation of the diazonium salt of compound (23), followed bytreatment of the in situ diazonium salt with CuCl₂ affords thecorresponding 5-chloro-1,2,4-oxadiazole (24). The bromo derivative couldalso be synthesized through the use of CuBr₂. Alternatively, alkylnitrile (21) can be converted into 5-chloro-1,2,4-oxadiazole (24) (WO95/005368) by reaction with hydroxylamine hydrochloride in anappropriate solvent such as methanol or ethanol, in the presence of anappropriate base such as triethylamine, Hunig's base, pyridine or sodiumacetate, followed by cyclization to a 1,2,4-oxadiazolone with abisacylating agent such as ethyl chloroformate, carbonyldiimidazole orphosgene. In certain embodiments, the cyclization requires the use of abase such as NaOH, NaH or triethylamine to allow for the formation ofthe 1,2,4-oxadiazolone. Reaction of the 1,2,4-oxadiazolone with adehydrating agent such as POCl₃, POBr₃ or PCl₅ affords the5-halo-1,2,4-oxadiazole (24). The oxadiazole intermediates (23) and (24)can be converted into a compound (3E) of Formula I by the methods shownin Scheme B.

Scheme H shows a method of preparing 2-aminooxazole and 2-halo-oxazoleintermediates (26) and (27), respectively, which are suitable for use inpreparing compounds of Formula I as shown in Scheme B. According toScheme H, α-hydroxyketone (25) is reacted with cyanamide to afford2-aminooxazole (26) (Aust. J. Chem. (1985), 38, 447-458). Formation ofthe diazonium salt of compound (26), followed by treatment of the insitu diazonium salt with CuX₂ (where X=Cl or Br) affords thecorresponding 5-halo-1,2,4-thiadiazole (27). Intermediates (26) and (27)can be converted into compound (3F) of Formula I by the method of SchemeB.

Scheme I shows a method of preparing compound (3G) of Formula I whereinZ is CR³. According to Scheme I, the halo-substituted heterocycle (28)(prepared by the method of Scheme A or B) wherein X¹=Cl, Br or I, isfirst treated with an appropriate amount of methyl lithium solution toremove exchangeable proton(s), and then transmetalated with an alkyllithium reagent such as n-BuLi, sec-butyl or tert-butyl lithium, or aGrignard reagent such as, i-PrMg-halide. The resulting anion is thenquenched with an electrophile to provide compound (3G). Suitableelectrophiles include, but are not limited to: 1) aldehydes, 2)nitriles, 3) N-methoxy-N-methylamides (Weinreb amides), 4)dialkylsulphides, 5) hexachloroethane, 6) trialkyl boronates, 7)sulphonyl chlorides, 8) sulfamyl chlorides, 9) isocyanates, 10) carbondioxide, (11) alkyl halides, (12) trifluoroiodomethane (13) Mander'sreagent, and (14) chloroformates. Exemplary compounds of the presentinvention which can be prepared according to the method of Scheme Iinclude compounds (3G) wherein R³ is alkyl, phenylalkyl, cycloalkyl,hydroxylalkyl (from R³Si(CH₂)_(n)I), Cl, SH, SR′, SOR′, SO₂R′, OR′, I,SCH₂R′, OCH₂R′, CO₂H, CH(OH)—R′, and C(═O)R′, wherein R′ is alkyl,alkenyl, alkynyl, cycloalkyl, or aryl.

Alternatively, the halo-substituted heterocycle (28) can be converted tocompound (3G) wherein R³ is alkyl, aryl, heteroaryl, alkenyl or alkynyl,by a metal (e.g., Cu or Pd) mediated coupling reaction such as, but notlimited to, the Negishi reaction, the Suzuki reaction, the Sonogashirareaction, or the Stille reaction.

Scheme J shows a method of preparing compounds (3H) of Formula I,wherein Z=C—SR³ or C—OR³, and Q=O or S, from a halo substitutedheterocycle (28). According to Scheme J, the halo-substitutedheterocycle (28), prepared by the method of Scheme A or B, can beconverted to a thiol or alcohol (29) by one of several procedures.According to one method, the halo-substituted heterocycle (28) is firsttreated with an appropriate amount of methyl lithium solution to removeexchangeable proton(s), and then transmetalated with an alkyl lithiumreagent such as n-BuLi, sec-butyl or tert-butyl lithium, or a Grignardreagent such as, i-PrMg-halide. The resulting anion is then quenchedwith either elemental sulfur or bis(trimethylsilyl)peroxide to form thecorresponding mercapto- or hydroxyl-substituted compound (29).Alternatively, the anion can be quenched with trimethyl borate andoxidized with either hydrogen peroxide (J. Med. Chem. (2004) 3089-3104)or N-methyl morpholine oxide (Syn. Lett. (1995) 931-932) to afford thephenol (29). As a third synthetic route, the halide (28) can beconverted under Pd-mediated conditions to thiol or phenol (29) utilizingpotassium triisopropylsilanethiolate (Tetrahedron Letters (1994)3225-3226) or sodium tert-butyldimethylsiloxide (J. Org. Chem., (2002)5553-5566). The thiol or phenol (29) can be alkylated with a variety ofelectrophiles using standard reaction conditions to provide thecorresponding ether (3H) of Formula I. Suitable electrophiles include,but are not limited to, alkyl halides, benzylic halides,heteraroyl-CH₂X, cycloalkyl halides, Michael acceptors, and activatedheteroaryl halides such as, but not limited to, 2-fluorocyanobenzene,4-fluorocyanobenzene, 2-fluoronitrobenzene, 4-fluoronitrobenzene,2-chloro-4-nitropyridine, 2-halopyridine, 2-halopyrimidine,4-halopyrimidine, aryl halides and heteroaryl halides.

Alternatively, halide (28) can be converted to an alkyl sulfide usingPd-mediated conditions with appropriately functionalized sulfides.Examples of such sulfides include, but are not limited to, esters of3-mercaptopropanoic acid, 3-mercaptopropanenitrile or2-(trimethylsilyl)ethanethiol. Sulfides of this type can be deprotectedto the thiol and alkylated with a variety of electrophiles understandard conditions (Chemical & Pharmaceutical Bulletin (1990), 38(10),2667-75).

Scheme K shows a method of adding a linker L, wherein L is O or S, to acore heterocycle to provide a compound (31) of Formula I wherein G=CR″,Z=C—Br, and Y=N. According to Scheme K, 2-amino-3,5-dibromopyrazine (30)is reacted with R²LH, wherein L is O or S, in the presence of a suitablebase such as K₂CO₃ or NaH in a suitable solvent such as DMF or ethanolto afford compound (31) regioselectively. Compound (31) can be convertedto compound (31) of Formula I by the method of Scheme A or B. Compound(31) can be converted into additional 5-substituted compounds of FormulaI by the methods shown in Scheme I or J.

Scheme L shows an alternate method of adding the linker OR² to a coreheterocycle to provide a compound (3) of Formula I wherein L is O.According to Scheme L, a benzyl ether (32), prepared by the method ofScheme A or B, can be converted to the hydroxyl substituted heterocycle(33), for example by hydrolysis with a strong acid (e.g., 6N HCl) or byhydrogenation (e.g., H₂ or ammonium formate in the presence of a metalcatalyst). Alkylation of the hydroxylated heterocycle (33) with R²X,wherein X=F, Cl, Br, I, or NR₃, in the presence of a base such as, butnot limited to, cesium carbonate, in a suitable solvent such as, but notlimited to, DMF, or by copper or palladium catalysis (i.e., the Ullmanreaction) affords compound (3) of Formula I.

Scheme M shows a method of preparing a compound (3J) of Formula Iwherein G=N, Z=CR³, Y=CH, and L=O or S. According to Scheme M,6-chloropyridazin-3-amine (34) is regioselectively brominated with asuitable brominating agent such as bromine, NBS, etc., to providecompound (35). Reaction of compound (35) with R²LH (wherein L is O or S)in the presence of a suitable base such cesium carbonate or sodiumhydride either with or without a metal catalyst (e.g., CuI) in DMSO orDMF regioselectively affords compound (36). Compound (36) can beconverted to the chlorinated compound (37) of Formula I by the method ofScheme A or B. Compound (37) can be converted into a 5-substitutedcompound (3J) of Formula I by the method of Scheme I or J.

Scheme N shows a method of preparing a compound (3L) of Formula Iwherein G=CR¹¹, Z=CR³, Y=CR⁴, and L is O or S. According to Scheme N,the 2-aminopyridine (38) is regioselectively brominated with a suitablebrominating agent such as NBS or bromine to provide compound (39). Thebrominated compound can be converted to compound (40) upon reaction withR²LH (wherein L is O or S) in the presence of a suitable base such ascesium carbonate, sodium hydride or triethylamine in the presence of ametal catalyst (i.e.; CuI or Pd₂dba₃) in a suitable solvent such as DMSOor DMF. The chlorinated product (40) can be converted to compound (41)by the method of Scheme A or B. Compound (41) can be converted to a5-substituted compound (3L) of Formula I by the method of Scheme I or J.Alternatively, the chlorinated 2-aminopyridine (40) can be converted toa 5-substituted compound (42) by the method of Scheme I or J, and thenthe heterocyclyl group R¹ can be added to compound (42) by the method ofScheme A or B to provide compound (3L).

Scheme O shows a method of preparing a compound (3L) of Formula Iwherein G=CR¹¹, Z=CR³, Y=CR⁴, and L is O or S. According to Scheme O,reaction of compound (43) with R²LH (wherein L is O or S) in thepresence of a suitable base such cesium carbonate or sodium hydrideeither with or without a metal catalyst (i.e.; Pd₂dba₃ or CuI) in DMSOor DMF affords compound (44) wherein L is O or S. Alternatively,reaction of compound (43) with R²CH₂Zn under similar conditions affordscompound (44) wherein L is CH₂. To prepare compound (44) wherein L isC═O, compound (43) can be treated to lithiation conditions as describedin Scheme 1, followed by treatment with R²CO(NMeOMe).

The 2-aminopyridine (44) is then regioselectively brominated with asuitable brominating agent such as NBS or bromine to provide compound(45). The brominated product (45) can be converted to compound (46) bythe method of Scheme A or B. Compound (46) can be converted to5-substituted compounds (3L) of Formula I by the method of Scheme I orJ. Alternatively, the brominated 2-aminopyridine (45) can be convertedto a 5-substituted compound (47) by the method of Scheme I or J, andthen the heterocyclyl group R¹ can be added to compound (47) by themethod of Scheme A or B to provide compound (3L).

Scheme P shows an alternative method of preparing a compound (3L) ofFormula I wherein G=CR¹¹, Z=CR³, Y=CR⁴, and L is O, S or CH₂. Accordingto Scheme P, reaction of compound (48) (which if not commerciallyavailable can be made from commercial aminopyridines by regioselectivebromination) in the presence of a suitable base such cesium carbonate orsodium hydride and with or without a metal catalyst (e.g., Pd₂dba₃ orCuI) in DMSO or DMF affords compound (49) by a method such as: ipsoreplacement (with R⁶OH or R⁶SH to provide compound (49) wherein R³ isOR⁶ or SR⁶, respectively); Buchwald ether or thioether formation (withR⁶OH or R⁶SH to provide compound (49) wherein R³ is OR⁶ or SR⁶,respectively); a Negishi reaction (with R³Zn); an aryl or alkyl Suzukireaction (with R³B(OH)₂); a Heck reaction, etc., according to procedureswell known in the literature and further exemplified in the Examplesbelow. The 2-aminopyridine (49) is then regioselectively brominated witha suitable brominating agent such as NBS or bromine to provide compound(50). The bromininated product (50) can be converted to compound (51) bythe method of Scheme A or B. Compound (51) can be converted to5-substituted compounds (3L) of Formula I by Buchwald ether or thioetherformation (with R²OH when L=O or R²SH when L=S), Negishi reactions (withR²CH₂Zn when L=CH₂), or by lithiation chemistry as described in Scheme I(when L is C═O) to provide compound (3L). Alternatively, the brominated2-aminopyridine (50) can first be converted to compound (52) by theBuchwald, Negishi, or lithiation chemistry, and compound (52) can beconverted to compound (3L) by the method of Scheme A or B.

Scheme Q shows a method of preparing a compound (3L) of Formula Iwherein G=CR¹¹, Z=CR³, Y=CR⁴ and L is O. Treatment of compound (53) withR²X in the presence of a suitable base such as cesium carbonate orsodium hydride, with or without a metal catalyst, affords compound 54.Examples of R²X that can be utilized include substituted 2- and4-nitrohalobenzenes, substituted 2- and 4-cyanohalobenzenes,2-chloro-1-fluorobenzene, halogenated pyridines, halogenatedpyrimidines, and other halogenated heterocycles. When R²X contains twohalogens, the halogen ortho or para to an electron withdrawing group isselectively displaced in preference to the meta substituted halogen, andthe leaving group potential using sodium hydride as a base is F>Cl>Br>I.In this way, a bromine-containing compound suitable for furtherfunctionalization can be made. For example using a brominated version of2-chloro-1-fluorobenzene with 3-hydroxy-2-amino pyridine affords abrominated version of compound (54). The bromine can be converted to avariety of functional groups at this stage to form other analogs ofcompound (54) using palladium mediated or anion chemistry. Subsequently,compound (54) can be regioselectively brominated to afford compound(55). This compound can be converted to compound (56) by the methodsdescribed in Schemes I or J. Compound (56) is then converted to compound(3L) by the procedures found in Schemes A or B. Alternatively, compound(55) can be converted to compound (57) by the procedures found inSchemes A or B, and then converted to compound (3L) by the proceduresfound in Schemes I or J.

Scheme R shows a method of preparing compounds of Formula I wherein R¹is a substituted thiazolyl. According to Scheme R,phthalimide-containing compound (58) wherein V is alkylene optionallysubstituted by one or more alkyl groups (which can be prepared by themethod of Scheme A or B), can be converted to amine (59) by treatmentwith hydrazine. Amine (59) can be elaborated to the amide, carbamate,urea, thiourea, monoalkylamine, dialkylamine, amidine, or guanidine (60)by routine methods in the literature.

Scheme S shows an alternative method of preparing compounds of Formula Iwherein R′ is a substituted thiazolyl. According to Scheme S, theester-containing compound (61), wherein V is alkylene optionallysubstituted by one or more alkyl groups (which can be prepared by themethod of Scheme A or B), can be converted to carboxylic acid (62) byreduction or hydrolysis with a hydride or hydroxide, respectively.Compound (62) can be converted to alcohol (64) upon treatment with alithium reagent R′Li. Alternatively, the carboxylic acid (62) can beconverted to a primary, secondary or tertiary amide (63) using a varietyof amide coupling methods known to those skilled in the art. Compound(62) can also be converted to compound (65), wherein R⁹ is aheterocyclyl group such as, but not limited to, tetrazolyl, imidazolyl,triazolyl, or thiazoyl, by coupling methods known to those skilled inthe art.

Scheme T describes the preparation of intermediates (68), (72) and (75)and substituted forms thereof suitable for use in preparing compounds ofFormula (3A) wherein R¹² and R¹³ form a fused heterocyclic ring. Toprepare intermediate (68), 2-halo-3-aminopyridine (66) is reacted with athiocyanate (for example, sodium or potassium thiocyanate) in acidicmedia (for example, acetic acid) to provide thiazolopyridine (67).Compound (67) is converted to the corresponding 2-halo compound (68) bystandard methods (for example, by diazotization of the amine with NaNO₂and HX³, followed by reaction with Cu(X³)₂).

To prepare intermediate (72), the 2-amino-3-halopyridazine (69) isreacted with a protected isothiocyanate to provide protected2-aminothiazolopyridazine (70), which is deprotected under standardhydrolytic conditions to provide 2-aminothiazolopyridazine (71) (Koren,B., et al., Heterocycles 1987, 26(3), 689-697). The aminoheterocycliccompound (71) is converted to the corresponding 2-halo compound (72),for example, as described above.

To prepare intermediate (75), compound (73) is converted to the2-aminothiazolotriazine (74), for example, using the method of Jacobsen,et al., (Aust. J. Chem. 1987, 40(3), 491-499). The aminoheterocycliccompound (74) is then converted to the corresponding 2-halo compound(75), for example, as described above.

It will be appreciated that the aminoheterocycles (68), (72) and (75)can be further functionalized if desired, for example by halogenation ofthe 6-membered ring (for example with NBS or bromine). Such halogenatedderivatives may be further modified using well known methods.

Scheme U shows an alternative method of preparing compounds of Formula(3A) wherein R² and R¹³ form a fused heterocyclic ring. Substituted2-halo-aminoheterocycles (76), wherein at least one X=N, but no morethan two consecutive X are N, is reacted with thiophosgene to providethe isothiocyanate (77). Refluxing the isothiocyanate (77) with the5-brominated aminopyridine (45) in a suitable solvent such as ethanol orTHF affords the heterocycle (78), which can be converted to compounds ofFormula (3A) by the methods described in Scheme P. Alternatively, theaminopyridine (47), prepared as in Scheme P, is refluxed with theisocyanate (77) to afford compounds of structure (3A).

Scheme V shows an alternative method for producing compounds of theformula 3C wherein D² is N. Formation of oxime (80) from aldehyde (79)allows for the chlorination with N-chlorosuccinimide in a suitablesolvent, such as DMF, to produce compound (81). Compound (81) issulfonylated with a sulfonyl chloride having the formula R′SO₂Cl whereinR′ is, C₁-C₆ alkyl (for example, methyl) or aryl optionally substitutedwith C₁-C₆ alkyl (for example, tolyl) in the presence of a base, such asbut not limited to triethylamine, to afford compound (82) (See, forexample, Gibbons, L. U.S. Pat. No. 3,983,246). Reaction of compound (82)with a thiocyanate salt, such as NaNCS, in a suitable solvent, such asacetonitrile, and in the presence of a base, such as but not limited topyridine, affords the activated intermediate (83) (see, for example,Takeuchi, K., JP 2001081084). Intermediate (83) can be reacted in situwith an appropriate amino heterocycle (7) to afford compounds of thestructure (3C) of Formula I.

Scheme W shows an alternative method for the construction of compoundsof Formula I where G and Y are CH, Z is C—SR⁶ or C—OR⁶, and L is O or S.Starting from the commercially available 2-cyanopyridine (84), selectivenucleophilic displacement can be achieved with compounds of the formulaR²Q¹H, where Q¹ is O or S, and an appropriate base, such as sodiumhydride, in a suitable solvent, such as DMF to provide compound (85).Addition of a second nucleophile having the formula R⁶Q²H, wherein Q² isO or S, under similar conditions, affords the functionalized2-cyanopyridine (86). Hydrolysis of the nitrile can occur under manyconditions, with NaOH in aqueous ethanol being preferred, to afford thepicolinate (87). Curtius rearrangement in the presence of an appropriatealcohol affords the carbamate (88). The carbamate can be removed usingvarious conditions, depending on the alcohol used in the previous step,to provide the 2-aminopyridine (89). Using procedures outlined inSchemes A, B or T, compounds (90) of the Formula I can be synthesizedfrom compound (89).

Accordingly, another embodiment of the invention provides a method forpreparing a compound of Formula I or a salt thereof, comprising:

(a) reacting a corresponding compound of the formula

with a compound of the formula R¹NH₂ in the presence of a base catalystor metal catalyst; or

(b) reacting a corresponding compound of the formula

with a compound of the formula R¹—X, wherein X is Cl or Br, in thepresence of a base catalyst or metal catalyst; or

(c) for a compound of Formula I wherein R′ is

reacting a corresponding compound of the formula

with a compound of the formula R¹³COCHR¹²X, wherein X is a leaving groupsuch as OTs, Cl, Br, I, or NR₃ and R is C₁-C₆ alkyl, in the presence ofa base; or

(d) for a compound of Formula I wherein R¹ is

reacting a corresponding compound of the formula

with a compound having the formula

where R′ is C₁-C₆ alkyl or aryl optionally substituted with C₁-C₆ alkyl,in the presence of a base; or

(e) for a compound of Formula I wherein Z is SR⁶, reacting acorresponding compound having the formula

with a compound having the formula R⁶SSR⁶ in the presence of a suitablebase, for example, an alkyl lithium such as methyl lithium, butyllithium, or a mixture thereof; or

(e) for a compound of Formula I wherein Z is SR⁶, reacting acorresponding compound having the formula

with a compound having the formula R⁶X wherein X is a leaving group oratom such as a halogen (e.g., F, Cl or Br) or a sulfonate (e.g., OMs orOTs) in the presence of a suitable base, for example an alkali metalalkoxide such as potassium t-butoxide; or

(f) for a compound of Formula I wherein R¹ is

reacting a corresponding compound having the formula

with a compound having the formula

in a suitable solvent, for example DMF, at elevated temperatures, forexample 80-110° C.; or

g) for a compound of Formula I wherein Z is CR³, reacting acorresponding compound having the formula

wherein X^(a) is a leaving group or atom (e.g., a halogen such as Br, Clor I,) with a compound having the formula R³X^(b) wherein X^(b) is aleaving group or atom, in the presence of a suitable base (e.g., analkyl lithium such as methyl lithium, butyl lithium, or a combinationthereof); or

h) for a compound of Formula I wherein Z is C—SR⁶ and R⁶ is alkyl,CH₂-aryl, heteroaryl, or aryl and wherein said R⁶ groups are optionallysubstituted, reacting a corresponding compound having the formula

with a compound having the formula R⁶—X¹ wherein X¹ is a leaving groupor atom (e.g., a halogen such as Cl or Br) in the presence of a suitablebase; or

i) for a compound of Formula I wherein L is O, reacting a correspondingcompound having the formula

with a compound having the formula R²—X^(d), wherein X^(d) is a leavinggroup or atom (e.g., a halogen such as Cl or Br; or a triflate ortosylate group), in the presence of a base (e.g., an alkali metalcarbonate such as CsCO₃) or in the presence of a copper or palladiumcatalyst; or

j) for a compound of Formula I wherein L is O or S, reacting acorresponding compound having the formula

wherein Xe is a leaving group or atom (e.g., Br, I or OTf) with acompound having the formula R²LH wherein L is O or S, respectively; inthe presence of a palladium catalyst (e.g., Pd(OAc)₂ and a ligand) and asuitable base (e.g., K₂CO₃, NaH, NaOt-Bu) and a suitable solvent (e.g.,toluene) at temperatures ranging from ambient temperature to 100° C.; or

k) for a compound of Formula I wherein L is CH₂, reacting acorresponding compound having the formula

wherein X¹ is a leaving group or atom (e.g., Cl, Br, I, OTf oracetyloxy) in the presence of an organozinc compound having the formulaR²—Zn—X^(g) wherein X^(g) is a halide (e.g., Cl, Br, or I) and a nickelor palladium catalyst; and

removing any protecting group or groups and, if desired, forming a salt.

In preparing compounds of Formula I, protection of remotefunctionalities (e.g., primary or secondary amines, etc.) ofintermediates may be necessary. The need for such protection will varydepending on the nature of the remote functionality and the conditionsof the preparation methods. Suitable amino-protecting groups (NH-Pg)include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC),benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Theneed for such protection is readily determined by one skilled in theart. For a general description of protecting groups and their use, seeT. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons,New York, 1991.

Methods of Separation

In any of the synthetic methods for preparing compounds of Formula I, itmay be advantageous to separate reaction products from one anotherand/or from starting materials. The desired products of each step orseries of steps is separated and/or purified to the desired degree ofhomogeneity by the techniques common in the art.

Methods of Treatment with Compounds of Formula I

The compounds of the present invention can be used as prophylactics ortherapeutic agents for treating diseases or disorders mediated bydeficient levels of glucokinase activity or which can be treated byactivating glucokinase including, but not limited to, diabetes mellitus,impaired glucose tolerance; IFG (impaired fasting glucose) and IFG(impaired fasting glycemia), as well as other diseases and disorderssuch as those discussed below. Furthermore, the compounds of the presentinvention can be also used to prevent the progression of the borderlinetype, impaired glucose tolerance, IFG (impaired fasting glucose) or IFG(impaired fasting glycemia) to diabetes mellitus.

Accordingly, another aspect of the invention provides methods oftreating or preventing diseases or conditions described herein byadministering to a mammal, such as a human, a therapeutically effectiveamount of a compound of Formula I.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein. The amount of a compound of Formula I thatwill correspond to such an amount will vary depending upon factors suchas the particular compound, disease condition and its severity, theidentity (e.g., weight) of the mammal in need of treatment, but cannevertheless be routinely determined by one skilled in the art.

The terms “treat” and “treatment” refer to both therapeutic treatmentand prophylactic or preventative measures, wherein the object is toprevent or slow down (lessen) an undesired physiological change ordisorder. For purposes of this invention, beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease, stabilized (i.e., not worsening)state of disease, delay or slowing of disease progression, ameliorationor palliation of the disease state, and remission (whether partial ortotal), whether detectable or undetectable. “Treatment” can also meanprolonging survival as compared to expected survival if not receivingtreatment. Those in need of treatment include those already with thecondition or disorder as well as those prone to have the condition ordisorder or those in which the condition or disorder is to be prevented.

As used herein, the term “mammal” refers to a warm-blooded animal thathas or is at risk of developing a disease described herein and includes,but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters,and primates, including humans.

In certain embodiments, the methods of this invention are useful fortreating diabetes mellitus. Diabetes mellitus is a condition where thefasting plasma glucose level (glucose concentration in venous plasma) isgreater than or equal to 126 mg/dL (tested on two occasions) and the2-hour plasma glucose level of a 75 g oral glucose tolerance test (OGTT)is greater than or equal to 200 mg/dL. Additional classic symptomsinclude polydipsia, polyphagia and polyuria.

In certain embodiments, the methods of this invention are useful fortreating the syndrome of impaired glucose tolerance (IGT). IGT isdiagnosed by the presentation of a fasting plasma glucose level of lessthan 126 mg/dL and a 2-hour post-oral glucose challenge lever greaterthan 140 mg/dL.

The compounds of the present invention can be also used as prophylacticsor therapeutic agents of diabetic complications such as, but not limitedto, neuropathy, nephropathy, retinopathy, cataract, macroangiopathy,osteopenia, diabetic hyperosmolar coma), infectious diseases (e.g.,respiratory infection, urinary tract infection, gastrointestinal tractinfection, dermal soft tissue infection, lower limb infection etc.),diabetic gangrene, xerostomia, decreased sense of hearing,cerebrovascular disease, peripheral circulatory disturbance, etc.

The compounds of the present invention can be, also used asprophylactics or therapeutic agents in the treatment of diseases anddisorders such as, but not limited to, obesity, metabolic syndrome(syndrome X), hyperinsulinemia, hyperinsulinemia-induced sensorydisorder, dyslipoproteinemia (abnormal lipoproteins in the blood)including diabetic dyslipidemia, hyperlipidemia, hyperlipoproteinemia(excess of lipoproteins in the blood) including type I, II-a(hypercholesterolemia), II-b, III, IV (hypertriglyceridemia) and V(hypertriglyceridemia), low IHDL levels, high LDL levels,atherosclerosis and its sequelae, vascular restenosis, neurodegenerativedisease, depression, CNS disorders, liver steatosis, osteoporosis,hypertension, renal diseases (e.g., diabetic nephropathy, glomerularnephritis, glomerulosclerosis, nephrotic syndrome, hypertensivenephrosclerosis, terminal renal disorder etc.), myocardiac infarction,angina pectoris, and cerebrovascular disease (e.g., cerebral infarction,cerebral apoplexy).

The compounds of the present invention can be also used as prophylacticsor therapeutic agents in the treatment of diseases and disorders suchas, but not limited to, osteoporosis, fatty liver, hypertension, insulinresistant syndrome, inflammatory diseases (e.g., chronic rheumatoidarthritis, spondylitis deformans, osteoarthritis, lumbago, gout,postoperative or traumatic inflammation, remission of swelling,neuralgia, pharyngolaryngitis, cystitis, hepatitis (includingnon-alcoholic steatohepatitis), pneumonia, inflammatory colitis,ulcerative colitis), pancreatitis, visceral obesity syndrome, cachexia(e.g., carcinomatous cachexia, tuberculous cachexia, diabetic cachexia,hemopathic cachexia, endocrinopathic cachexia, infectious cachexia,cachexia induced by acquired immunodeficiency syndrome), polycysticovary syndrome, muscular dystrophy, tumor (e.g., leukemia, breastcancer, prostate cancer, skin cancer etc.), irritable bowel syndrome,acute or chronic diarrhea, spondylitis deformans, osteoarthritis,remission of swelling, neuralgia, pharyngolaryngitis, cystitis, SIDS,and the like.

This invention also provides the use of a compound of Formula I in thetreatment of diseases or disorders mediated by deficient levels ofglucokinase activity or which can be treated by activating glucokinase.

An additional aspect of the invention is the use of a compound ofFormula I in the preparation of a medicament for the treatment orprevention of diseases or disorders mediated by deficient levels ofglucokinase activity or which can be treated by activating glucokinase.

Combination Therapy

The compounds of the present invention can be used in combination withone or more additional drugs such as described below. The dose of thesecond drug can be appropriately selected based on a clinically employeddose. The proportion of the compound of the present invention and thesecond drug can be appropriately determined according to theadministration subject, the administration route, the target disease,the clinical condition, the combination, and other factors. In caseswhere the administration subject is a human, for instance, the seconddrug may be used in an amount of 0.01 to 100 parts by weight per part byweight of the compound of the present invention.

The second compound of the pharmaceutical combination formulation ordosing regimen preferably has complementary activities to the compoundof this invention such that they do not adversely affect each other.Such drugs are suitably present in combination in amounts that areeffective for the purpose intended. Accordingly, another aspect of thepresent invention provides a composition comprising a compound of thisinvention in combination with a second drug, such as described herein.

A compound of this invention and the additional pharmaceutically activeagent(s) may be administered together in a unitary pharmaceuticalcomposition or separately and, when administered separately this mayoccur simultaneously or sequentially in any order. Such sequentialadministration may be close in time or remote in time. The amounts ofthe compound of this invention and the second agent(s) and the relativetimings of administration will be selected in order to achieve thedesired combined therapeutic effect.

The combination therapy may provide “synergy” and prove “synergistic”,i.e., the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined, unit dosage formulation; (2) delivered byalternation or in parallel as separate formulations; or (3) by someother regimen. When delivered in alternation therapy, a synergisticeffect may be attained when the compounds are administered or deliveredsequentially, e.g., by different injections in separate syringes. Ingeneral, during alternation therapy, an effective dosage of each activeingredient is administered sequentially, i.e., serially, whereas incombination therapy, effective dosages of two or more active ingredientsare administered together.

The compounds of the present invention can be used, for example, incombination with additional drug(s) such as a therapeutic agent fordiabetes mellitus, and/or a therapeutic agent for diabeticcomplications, as defined above. Examples of known therapeutic agentsfor diabetes mellitus which can be used in combination with a compoundof this invention include insulin preparations (e.g., animal insulinpreparations extracted from the bovine or swine pancreas; human insulinpreparations synthesized by a genetic engineering technique usingEscherichia coli or a yeast), a fragment of insulin or derivativesthereof (e.g., INS-1), agents for improving insulin resistance (e.g.,pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate,GI-262570, JTT-501, MCC-555, YM-440, KRP-297, CS-011, FK-614),alpha-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol,emiglitate), biguanides (e.g., phenformin, metformin, buformin), insulinsecretagogues [sulfonylureas (e.g., tolbutamide, glibenclamide,gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide,glimepiride, glipizide, glybuzole), repaglinide, nateglinide,mitiglinide or its calcium salt hydrate, GLP-1], dipeptidylpeptidase IVinhibitors (e.g., NVP-DPP-278, PT-100), beta-3 agonists (e.g.,CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085,AZ-40140, etc.), amylin agonists (e.g., pramlintide), phosphotyrosinephosphatase inhibitors (e.g., vanadic acid), gluconeogenesis inhibitors(e.g., glycogen phosphorylase inhibitors, glucose-6-phosphataseinhibitors, glucagon antagonists), SGLT (sodium-glucose cotransporter)inhibitors (e.g., T-1095), and the like.

Examples of known therapeutic agents for diabetic complications includealdose reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat,zopolrestat, minalrestat, fidarestat (SNK-860), CT-112), neurotrophicfactors (e.g., NGF, NT-3, BDNF), neurotrophic factor productionsecretion promoters, PKC inhibitors (e.g., LY-333531), AGE inhibitors(e.g., ALT946, pimagedine, pyratoxathine, N-phenacylthiazolium bromide(ALT766), EXO-226), active oxygen scavengers (e.g., thioctic acid), andcerebral vasodilators (e.g., tiapuride, mexiletine).

The compounds of the present invention can also be used, for example incombination with antihyperlipidemic agents. Epidemiological evidence hasfirmly established hyperlipidemia as a primary risk factor in causingcardiovascular disease (CVD) due to atherosclerosis. In recent years,emphasis has been placed on lowering plasma cholesterol levels, and lowdensity lipoprotein cholesterol in particular, as an essential step inprevention of CVD. Cardiovascular disease is especially prevalent amongdiabetic subjects, at least in part because of the existence of multipleindependent risk factors in this population. Successful treatment ofhyperlipidemia in the general population, and in diabetic subjects inparticular, is therefore of exceptional medical importance. Examples ofantihyperlipidemic agents include, but are not limited to, statincompounds which are cholesterol synthesis inhibitors (e.g.,cerivastatin, pravastatin, simvastatin, lovastatin, atorvastatin,fluvastatin, itavastatin or their salts, etc.), squalene synthaseinhibitors or fibrate compounds (e.g., bezafibrate, clofibrate,simfibrate, clinofibrate) having a triglyceride lowering action and thelike.

The compounds of the present invention can also be used, for example, incombination with hypotensive agents. Hypertension has been associatedwith elevated blood insulin levels, a condition known ashyperinsulinemia. Insulin, a peptide hormone whose primary actions areto promote glucose utilization, protein synthesis and the formation andstorage of neutral lipids, also acts to promote vascular cell growth andincrease renal sodium retention, among other things. These latterfunctions can be accomplished without affecting glucose levels and areknown causes of hypertension. Peripheral vasculature growth, forexample, can cause constriction of peripheral capillaries, while sodiumretention increases blood volume. Thus, the lowering of insulin levelsin hyperinsulinemics can prevent abnormal vascular growth and renalsodium retention caused by high insulin levels and thereby alleviateshypertension. Examples of hypotensive agents include, but are notlimited to, angiotensin converting enzyme inhibitors (e.g., captopril,enalapril, delapril), angiotensin II antagonists (e.g., candesartancilexetil, losartan, eprosartan, valsantan, termisartan, irbesartan,tasosartan), calcium antagonists (e.g., manidipine, nifedipine,nicardipine, amlodipine, efonidipine), and clonidine.

The compounds of the present invention can be used in combination withantiobesity agents. The term “obesity” implies an excess of adiposetissue. Obesity is a well-known risk factor for the development of manyvery common diseases such as diabetes, atherosclerosis, andhypertension. To some extent appetite is controlled by discrete areas inthe hypothalamus: a feeding centre in the ventrolateral nucleus of thehypothalamus (VLH) and a satiety centre in the ventromedial hypothalamus(VMH). The cerebral cortex receives positive signals from the feedingcenter that stimulate eating, and the satiety center modulates thisprocess by sending inhibitory impulses to the feeding center. Severalregulatory processes may influence these hypothalamic centers. Thesatiety center may be activated by the increases in plasma glucoseand/or insulin that follow a meal. Examples of antiobesity agentsinclude, but are not limited to; antiobesity drugs acting on the centralnervous system (e.g., dexfenfluramine, fenfluramine, phentermine,sibutramine, anfepramon, dexamphetamine, mazindol, phenylpropanolamine,clobenzolex), pancreatic lipase inhibitors (e.g. orlistat), beta-3agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677,BMS-196085, AZ-40140), anorectic peptides (e.g.; leptin, CNTF (CiliaryNeurotrophic Factor) and cholecystokinin agonists (e.g. lintitript,FPL-15849).

Routes of Administration

The compounds of the invention may be administered by any routeappropriate to the condition to be treated. Suitable routes includeoral, parenteral (including subcutaneous, intramuscular, intravenous,intraarterial, intradermal, intrathecal and epidural), transdermal,rectal, nasal, topical (including buccal and sublingual), vaginal,intraperitoneal, intrapulmonary and intranasal. It will be appreciatedthat the preferred route may vary with, for example, the condition ofthe recipient. Where the compound is administered orally, it may beformulated as a pill, capsule, tablet, etc. with a pharmaceuticallyacceptable carrier or excipient. Where the compound is administeredparenterally, it may be formulated with a pharmaceutically acceptableparenteral vehicle and in a unit dosage injectable form, as detailedbelow.

Pharmaceutical Formulations

In order to use a compound of this invention for the therapeutictreatment (including prophylactic treatment) of mammals includinghumans, it is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition. According tothis aspect of the invention there is provided a pharmaceuticalcomposition that comprises a compound of this invention in associationwith a pharmaceutically acceptable diluent or carrier.

In another embodiment of the invention, an article of manufacture, or“kit”, containing materials useful for the treatment of the disordersdescribed above is provided. In one embodiment, the kit comprises acontainer comprising a compound of this invention. Suitable containersinclude, for example, bottles, vials, syringes, blister pack, etc. Thecontainer may be formed from a variety of materials such as glass orplastic. The container may hold a compound of this invention or aformulation thereof which is effective for treating the condition andmay have a sterile access port (for example, the container may be anintravenous solution bag or a vial having a stopper pierceable by ahypodermic injection needle).

EXAMPLES

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare a numberof other glucokinase activators of the invention, and alternativemethods for preparing the compounds of this invention are deemed to bewithin the scope of this invention. For example, the synthesis ofnon-exemplified compounds according to the invention may be successfullyperformed by modifications apparent to those skilled in the art, e.g.,by appropriately protecting interfering groups, by utilizing othersuitable reagents known in the art other than those described, and/or bymaking routine modifications of reaction conditions. Alternatively,other reactions disclosed herein or known in the art will be recognizedas having applicability for preparing other compounds of the invention.

The compounds of this invention also include the compounds of Examples1-478 described below, with the exception of the examples labeled as“reference examples”. Compounds labeled “Reference Examples” were foundto be weakly active in the in vitro assays described below, and areprovided to illustrate representative methodology in preparing compoundsof Formula I.

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company, Lancaster,TCI or Maybridge, and were used without further purification unlessotherwise indicated.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsby syringe. Glassware was oven dried and/or heat dried.

Column chromatography was done on a Biotage system (Manufacturer: DyaxCorporation) having a silica gel column or on a silica SepPak cartridge(Waters). ¹H NMR spectra were recorded on a Varian instrument operatingat 400 MHz. ¹H NMR spectra were obtained as CDCl₃ or d₆-DMSO solutions(reported in ppm), using (7.25 ppm) or tetramethylsilane (0.00 ppm) asthe reference standard (7.25 ppm). When peak multiplicities arereported, the following abbreviations are used: s (singlet), d(doublet), t (triplet), m (multiplet), br (broadened), dd (doublet ofdoublets), dt (doublet of triplets). Coupling constants, when given, arereported in Hertz (Hz).

Example 1 2-(2-(4-Methylthiazol-2-ylamino)pyridin-3-yloxy)benzonitrile

Step A: 2-(2-chloropyridin-3-yloxy)benzonitrile: A 50 mL round bottomflask was charged with 2-chloropyridin-3-ol (2.5 g, 19 mmol),2-fluorobenzonitrile (2.6 g, 21 mmol) and potassium carbonate (6.7 g, 48mmol) in DMF (10 mL) and heated at 90° C. for 1.5 days. Water was addedwater, and the reaction mixture was extracted with ethyl acetate, driedover magnesium sulfate, filtered and concentrated. The residue waspurified by silica gel column chromatography using 10-20% ethyl acetatein hexanes as eluent to afford the title compound as an off white solid(2.1 g, 47% yield).

Step B: 2-(2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)benzonitrile: A50 mL round bottom flask was charged with2-(2-chloropyridin-3-yloxy)benzonitrile (0.667 g, 2.89 mmol),4-methylthiazol-2-amine (0.300 g, 2.63 mmol), potassium phosphate (0.614g, 2.89 mmol) and toluene (7 mL). The reaction mixture was degassed withnitrogen. Tris(dibenzylideneacetone)-dipalladium (0) (0.0602 g, 0.0657mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.0418 g,0.0723 mmol) were added, and the reaction mixture was degassed withnitrogen. The reaction mixture was warmed to 90° C. and degassed water(2 mL) was added. The reaction mixture was stirred at 90° C. overnight.Water was added and the reaction mixture was extracted with ethylacetate. The organic layer was dried over magnesium sulfate, filteredand concentrated. The residue was purified by silica gel columnchromatography using 10-40% ethyl acetate in hexanes as eluent to affordthe title compound as a yellow solid (0.385 g, 46.6% yield). ¹H NMR(CDCl₃) δ 8.19 (dd, 1H), 7.68 (dd, 1H), 7.49 (m, 1H), 7.19 (dd, 1H),7.15 (dd, 1H), 6.85 (m, 2H), 6.39 (m, 1H), 2.29 (d, 3H); Mass spectrum(esi) m/z=309 (100).

Example 2 4-(2-(4-Methylthiazol-2-ylamino)pyridin-3-yloxy)benzonitrile

Prepared according to the method of Example 1, starting with4-(2-chloropyridin-3-yloxy)benzonitrile. ¹H NMR (CDCl₃) δ 8.19 (dd, 1H),7.62 (m, 1H), 7.59 (m, 1H), 7.21 (dd, 1H), 7.02 (m, 1H), 7.00 (m, 1H),6.87 (dd, 1H), 6.39 (m, 1H), 2.28 (d, 3H); Mass spectrum (esi) m/z=309(100).

Example 32-(2-(3-Methyl-1,2,4-thiadiazol-5-ylamino)pyridin-3-yloxy)benzonitrile

Prepared according to the method of Example 1, Step B, starting with2-(2-chloropyridin-3-yloxy)benzonitrile. ¹H NMR (CDCl₃) δ 9.14 (bs, 1H),8.28 (dd, 1H), 7.73 (dd, 1H), 7.56 (m, 1H), 7.24-7.29 (m, 2H), 7.00 (dd,1H), 6.94 (d, 1H) 2.52 (s, 3H); Mass spectrum (esi) m/z=310 (100).

Example 4 Representative ExampleN-(4-methylthiazol-2-yl)-3-(2-nitrophenoxy)pyridin-2-amine

Prepared according to the method of Example 1, Step B, starting with4-methylthiazol-2-amine. ¹H NMR (CDCl₃) δ 10.12 (bs, 1H), 8.13 (m, 1H),7.84 (dd, 1H), 7.71 (dt, 1H), 7.59 (m, 2H), 7.41 (dd, 1H), 7.11 (dd,1H), 6.23 (m, 1H), 2.28 (d, 3H); Mass spectrum (esi) m/z=329 (100).

Example 5 N-(4-Methylthiazol-2-yl)-3-(4-nitrophenoxy)pyridin-2-amine

Prepared according to the method of Example 1, Step B, starting with4-methylthiazol-2-amine. ¹H NMR (CDCl₃) δ 9.30 (bs, 1H), 8.24 (m, 1H),8.22 (m, 1H), 8.00 (dd, 1H), 7.44 (dd, 1H), 7.33 (m, 1H), 7.30 (m, 1H),7.21 (dd, 1H), 6.53 (m, 1H), 2.36 (d, 3H); Mass spectrum (esi) m/z=329(100).

Example 63-(4-(Methylsulfonyl)phenoxy)-N-(4-methylthiazol-2-yl)pyridin-2-aminehydrochloride

Prepared according to the method of Example 1, starting with2-chloro-3-(4-(methylsulfonyl)phenoxy)pyridine. ¹H NMR (CDCl₃) δ 8.28(dd, 1H), 7.94 (m, 1H), 7.92 (m, 1H), 7.63 (dd, 1H), 7.23 (m, 1H), 7.21(m, 1H), 7.13 (dd, 1H), 6.74 (bs, 1H), 3.20 (s, 3H), 2.26 (d, 3H); Massspectrum (esi) m/z=362 (100).

Example 7 5-Chloro-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine

Step A: 3-bromo-5-chloropyridin-2-amine: A 250 mL round-bottomed flaskwas charged with 5-chloropyridin-2-amine (80 g, 622.3 mmol) and CHCl₃(100 mL). Added bromine (31.98 mL, 622.3 mmol) and stirred at roomtemperature for 30 minutes. The reaction mixture was poured intosaturated bicarbonate and NaHSO₃ and extracted with CH₂Cl₂. The organiclayer was dried with sodium sulfate, filtered and concentrated to affordthe title compound (113.8 g, 88.1% yield) as a tan solid. ¹H NMR(d₆-DMSO) δ 7.97 (d, 1H), 7.90 (d, 1H), 6.44 (bs, 2H).

Step B: 5-chloro-3-phenoxypyridin-2-amine:3-Bromo-5-chloropyridin-2-amine (50.0 g, 241 mmol), phenol (45.4 g, 482mmol), copper(I)oxide (1.72 g, 12.1 mmol), (E)-2-hydroxybenzaldehydeoxime (6.61 g, 48.2 mmol), Cs₂CO₃ (157 g, 482 mmol), and 3A powderedmolecular (72.3 g) sieves were placed in DMF (300 mL) and heated at 110°C. for 3 days. Reaction was cooled, then filtered through celite.Reaction was then partitioned between water and ether. An emulsion wasformed and was filtered through a plug of celite. Water was extractedwith ether then dried, filtered, and concentrated. Crude material waspurified on a first silica gel chromatography (5-10% EtOAc in hexanes),and then on a second column to provide the title compound (8.00 g, 15.0%yield). ¹H NMR (CDCl₃) δ 7.80 (d, 1H), 7.39 (t, 2H), 7.19 (t, 1H), 7.03(d, 2H), 6.94 (d, 1H), 4.76 (bs, 2H); Mass spectrum (apci) m/z=221(100).

Step C: 1-benzoyl-3-(5-chloro-3-phenoxypyridin-2-yl)thiourea:5-chloro-3-phenoxypyridin-2-amine (8.493 g, 38.490 mmol) and benzoylisothiocyanate (6.9096 g, 42.339 mmol) were placed in THF (200 mL) andstirred at room temperature for 2 hours. THF was removed. A suspensionwas made by adding Hexanes:EtOAc (9:1). The suspension was filtered andthe solid was washed with hexanes then dried to afford the titlecompound (13.752 g, 93.1% yield) as a yellow solid. ¹H NMR (d₆-DMSO) δ12.35 (s, 1H), 11.84 (s, 1H), 8.34 (d, 1H), 7.95 (d, 2H), 7.66 (t, 1H),7.53 (t, 2H), 7.44 (m, 3H), 7.24 (t, 1H), 7.18 (m, 2H); Mass spectrum(apci) m/z=383.1 (M+H).

Step D: 1-(5-chloro-3-phenoxypyridin-2-yl)thiourea: A 250 mLround-bottomed flask was charged with1-benzoyl-3-(5-chloro-3-phenoxypyridin-2-yl)thiourea (13.752 g, 35.826mmol) and THF (100 mL). 3M NaOH (119.42 mL, 358.26 mmol) was added andthe reaction mixture was heated to 90° C. for 18 hours. The reactionmixture was cooled to room temperature and concentrated. The resultingsolids were filtered, washed with water, and dried to provide the titlecompound (9.49 g, 94.689% yield) as a yellow solid. ¹H NMR (d₆-DMSO) δ9.97 (s, 1H), 9.25 (s, 1H), 8.87 (s, 1H), 8.11 (d, 1H), 7.49 (t, 2H),7.31 (d, 1H), 7.28 (m, 2H), 7.23 (d, 2H); Mass spectrum (apci) m/z=279.9(M+H).

Step E: 5-chloro-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine: Amixture of 1-chloropropan-2-one (3.827 g, 41.36 mmol),1-(5-chloro-3-phenoxypyridin-2-yl)thiourea (8.265 g, 29.54 mmol),triethylamine (7.001 mL, 50.23 mmol), and ethanol (30 mL) was refluxedfor 3 hours. The ethanol was removed to about one third original volume,and then the reaction mixture was cooled in an ice bath and filtered.The solids were washed with cold ethanol and dried to afford the titlecompound (8.35 g, 88.96% yield) as a light yellow powder. ¹H NMR(d₆-DMSO) δ 10.94 (bs, 1H), 8.15 (d, 1H), 7.43 (t, 2H), 7.32 (d, 1H),7.20 (t, 1H), 7.19 (d, 2H), 6.60 (s, 1H), 2.23 (s, 3H); Mass spectrum(apci) m/z=318.2 (M+H).

Example 8N-(4-methylthiazol-2-yl)-3-phenoxy-5-(phenylthio)pyridin-2-aminehydrochloride

5-Chloro-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine (0.150 g,0.472 mmol) was placed in THF (30 mL) and cooled to −78° C. MeLi (0.369mL, 0.590 mmol) was slowly added and the reaction mixture was stirredfor 10 minutes. Butyllithium (0.236 mL, 0.590 mmol) was added and thereaction mixture was stirred for 30 minutes. 1,2-Diphenyldisulfane(0.103 g, 0.472 mmol) was added and the reaction mixture was warmed toroom temperature, then stirred for 15 minutes. The reaction mixture wasquenched with ammonium chloride and extracted with CH₂Cl₂. The organiclayer was dried, filtered, and concentrated. The residue was purified bysilica gel chromatography (10-20% EtOAc in hexanes), and then by reversephase chromatography to give the title compound (0.0572 g, 28.3% yield)after salt formation. ¹H NMR (d₆-DMSO) δ 10.94 (bs, 1H), 8.15 (d, 1H),7.43 (t, 2H), 7.32 (d, 1H), 7.20 (t, 1H), 7.19 (d, 2H), 6.60 (s, 1H),2.23 (s, 3H); Mass spectrum (apci) m/z=392.2 (M+H—HCl).

Example 9 N-(4-methylthiazol-2-1)-3-phenoxy-5-phenylpyridin-2-aminehydrochloride

5-Chloro-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine (0.150 g,0.472 mmol), phenylboronic acid (0.0691 g, 0.566 mmol), Pd(PPh₃)₄(0.0545 g, 0.0472 mmol), in DME (10 mL), and 2M Na₂CO₃ (5 mL) wereplaced in a round bottom flask, heated to 80° C. and stirred overnight.An extra equivalent of Pd(PPh₃)₄ (0.0545 g, 0.0472 mmol), andphenylboronic acid (0.0691 g, 0.566 mmol) were added and the reactionmixture was heated for 2 weeks. The reaction mixture was cooled to roomtemperature and partitioned between CH₂Cl₂ and water. The organic layerwas dried, filtered, and concentrated. The residue was purified bysilica gel chromatography and then by reverse phase chromatography togive the title compound (0.0134 g, 7.17% yield) after salt formation. ¹HNMR (d₆-DMSO) δ 8.53 (d, 1H), 7.65 (m, 3H), 7.45 (m, 4H), 7.37 (m, 1H),7.21 (t, 1H), 7.16 (d, 2H), 6.78 (s, 1H), 2.29 (s, 3H); Mass spectrum(apci) m/z=360.3 (M+H—HCl).

Example 10 5-Bromo-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine

Step A: 3-phenoxypyridin-2-amine: Prepared according to the method ofExample 7 Step A, starting with bromopyridin-2-amine, phenol, and(E)-2-hydroxybenzaldehyde oxime (20.61 g, 150.3 mmol).

Step B: 5-bromo-3-phenoxypyridin-2-amine: 3-Phenoxypyridin-2-amine(20.50 g, 110.1 mmol) was placed in acetic acid (50 mL) and cooled to 0°C. Bromine (d 3.12) (7.049 mL, 137.6 mmol) was slowly added and thereaction mixture was stirred for 1 hour. The reaction mixture was pouredonto saturated sodium bisulfite and ice and allowed to sit overnight.Solids were removed by filtration and washed with water to give pure5-bromo-3-phenoxypyridin-2-amine. The filtrate was then extracted withCH₂Cl₂ several times, combined, and washed with water. Organic layer wasdried, filtered, and concentrated. The residue was purified by silicagel (5-20% EtOAc in hexanes) to give additional5-bromo-3-phenoxypyridin-2-amine (total yield: 22.69 g, 77.74% yield).

Step C: 1-benzoyl-3-(5-bromo-3-phenoxypyridin-2-yl)thiourea: Preparedaccording to the method of Example 7 Step C.

Step D: 1-(5-bromo-3-phenoxypyridin-2-yl)thiourea: Prepared according tothe method of Example 7 Step D.

Step E 5-bromo-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine:Prepared according to the method of Example 7 Step E, using1-chloropropan-2-one. ¹H NMR (d₆-DMSO) δ 10.90 (bs, 1H), 8.21 (d, 1H),7.43 (t, 2H), 7.39 (d, 1H), 7.20 (t, 1H), 7.09 (d, 2H), 6.61 (s, 1H),2.23 (s, 3H); Mass spectrum (apci) m/z=364.1 (M+H).

Example 11N-(4-methylthiazol-2-yl)-3-phenoxy-5-(pyridin-3-yl)pyridin-2-aminedihydrochloride

5-Bromo-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine (0.070 g,0.1932 mmol), pyridin-3-ylboronic acid (0.02850 g, 0.2319 mmol),Pd(PPh₃)₄ (0.02233 g, 0.01932 mmol), DME (10 mL), and 2M sodiumbicarbonate (2 mL) were combined, heated to 80° C. and stirredovernight. The reaction mixture was cooled and partitioned betweenCH₂Cl₂ and water. The organic layer was dried, filtered, andconcentrated. The residue was purified by silica gel chromatography(30-40% EtOAc in hexane) to giveN-(4-methylthiazol-2-yl)-3-phenoxy-5-(pyridin-3-yl)pyridin-2-amine.N-(4-methylthiazol-2-yl)-3-phenoxy-5-(pyridin-3-yl)pyridin-2-amine wasdissolved in CH₂Cl₂ and 2M HCl in ether was added to giveN-(4-methylthiazol-2-yl)-3-phenoxy-5-(pyridin-3-yl)pyridin-2-aminedihydrochloride (0.050 g, 59.71% yield). ¹H NMR (d₆-DMSO) δ 9.19 (d,1H), 8.78 (dd, 1H), 8.70 (m, 2H), 7.93 (m, 2H), 7.42 (t, 2H), 7.18 (t,1H), 7.12 (d, 2H), 6.74 (s, 1H), 2.28 (s, 3H); Mass spectrum (apci)m/z=361.2 (M+H-2HCl).

Example 12N-(4-methylthiazol-2-yl)-3-phenoxy-5-(pyridin-4-yl)pyridin-2-aminedihydrochloride

Prepared according to the method of Example 1-1, using5-bromo-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine andpyridin-4-ylboronic acid. ¹H NMR (d₆-DMSO) δ 8.96 (d, 1H), 8.86 (d, 2H),8.05 (d, 1H), 7.42 (t, 2H), 7.17 (t, 1H), 7.17 (t, 1H), 7.10 (d, 2H),6.73 (s, 1H), 2.26 (s, 3H); Mass spectrum (apci) m/z=361.3 (M+H-2HCl).

Example 13 Methyl3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate

A 25 mL round-bottomed flask was charged with5-bromo-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine (350 mg, 0.966mmol), Pd₂dba₃ (22.1 mg, 0.024 mmol),4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (27.9 mg, 0.048mmol), N-ethyl-N-isopropylpropan-2-amine (0.33 mL, 1.9 mmol), methyl3-mercaptopropanoate (0.12 mL, 1.1 mmol), and dioxane (10 mL). Thereaction mixture was heated to 100° C. under nitrogen for 2 hours. Thereaction mixture was cooled to room temperature, filtered andconcentrated. The residue was purified by silica gel chromatography (40%EtOAc in hexanes) to afford the title compound (328 mg, 84.5% yield) asa pale yellow solid. HCl salt made for characterization. ¹H NMR(d₆-DMSO) 8.18 (d, 1H), 7.45 (m, 2H), 7.36 (d, 1H), 7.22 (t, 1H), 7.13(d, 2H), 6.79 (s, 1H), 3.55 (s, 3H), 3.07 (t, 2H), 2.57 (t, 2H), 2.29(s, 3H); Mass spectrum (esi) m/z=402.2 (100)(M+H—HCl).

Example 14N-(5-(cyclohexylthio)-3-phenoxypyridin-2-yl)-4-methylthiazol-2-aminehydrochloride

Prepared according to the method of Example 13, using5-bromo-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine andcyclohexanethiol. ¹H NMR (d₆-DMSO) δ 8.17 (d, 1H), 7.45 (m, 2H), 7.30(d, 1H), 7.22 (t, 1H), 7.13 (m, 2H), 6.80 (s, 1H), 3.08 (m, 1H), 2.29(s, 3H), 1.82 (m, 2H), 1.66 (m, 2H), 1.52 (m, 1H), 1.23 (m, 5H); Massspectrum (esi) m/z=398.2 (100)(M+H—HCl).

Example 15N-(5-(benzylthio)-3-phenoxypyridin-2-v)-4-methylthiazol-2-aminehydrochloride

Prepared according to the method of Example 13, using5-bromo-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine andphenylmethanethiol. ¹H NMR (d₆-DMSO) δ 8.08 (d, 1H), 7.42 (m, 2H),7.28-7.15 (m, 7H), 6.98 (m, 21H), 6.74 (s, 1H), 4.12 (s, 2H), 2.27 (s,3H); Mass spectrum (esi) m/z=406.2 (100) (M+H—HCl).

Example 164-Methyl-N-(3-phenoxy-5-(pyridin-2-ylmethylthio)pyridin-2-yl)thiazol-2-aminedihydrochloride

A 20 mL vial was charged with methyl3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate(135.8 mg, 0.338 mmol) and THF (0.5 mL). 1M KOtBu in THF (1.184 mL,1.184 mmol) was added and the reaction mixture was stirred at roomtemperature for 30 seconds. 2-(Bromomethyl)pyridine hydrobromide (85.55mg, 0.3382 mmol) was added and the reaction mixture was stirred at roomtemperature for 30 minutes. Saturated aqueous ammonium chloride wasadded and the reaction mixture was extracted with EtOAc. Theconcentrated residue was purified on silica gel to affordN-(4-methylthiazol-2-yl)-3-phenoxy-5-(pyridin-2-ylmethylthio)pyridin-2-aminedihydrochloride (98.2 mg, 60.5% yield) as a pale yellow solid after HClsalt formation. ¹H NMR (d₆-DMSO) δ 8.66 (dd, 1H), 8.22 (td, 1H), 8.12(d, 1H), 7.70 (t, 1H), 7.62 (d, 1H), 7.45 (m, 2H), 7.23 (t, 1H), 7.16(d, 1H), 7.06 (m, 2H), 6.82 (m, 1H), 4.42 (s, 2H), 2.29 (s, 3H); Massspectrum (esi) m/z=407.2 (100) (M+H-2HCl).

Example 174-Methyl-N-(3-phenoxy-5-(piperidin-4-ylmethylthio)pyridin-2-yl)thiazol-2-aminedihydrochloride

Prepared according to the method of Example 16, using methyl3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate.¹H NMR (d₆-DMSO) δ 8.83 (m, 1H), 8.52 (m, 1H), 8.18 (dd, 1H), 7.43 (m,2H), 7.36 (dd, 1H), 7.20 (td, 1H), 7.10 (m, 2H), 6.72 (s, 1H), 3.57 (d,1H), 3.21 (m, 2H), 2.86 (m, 2H), 2.79 (m, 2H), 2.26 (s, 3H), 1.87 (m,2H), 1.67 (m, 1H), 1.35 (m, 2H); Mass spectrum (esi) m/z=413.1(100)(M+H-2HCl).

Example 18 N-(5-Chloro-3-phenoxypyridin-2-yl)-4-ethylthiazol-2-amine

Prepared according to the method of Example 7, using 1-bromobutan-2-one.Mass spectrum (esi) m/z=332 (100), 334 (38).

Example 19N-(5-chloro-3-phenoxypyridin-2-yl)-4,5-dimethylthiazol-2-amine

Prepared according to the method of Example 7, using3-chlorobutan-2-one. ¹H NMR (d₆-DMSO) δ 10.78 (bs, 1H), 8.11 (s, 1H),7.42 (t, 2H), 7.29 (s, 1H), 7.19 (t, 1H), 7.09 (d, 2H), 2.22 (s, 3H),2.12 (s, 3H); Mass spectrum (esi) m/z=332 (100), 334 (38).

Example 20 N-(5-Chloro-3-phenoxypyridin-2-yl)-4-isobutylthiazol-2-amine

Prepared according to the method of Example 7, using1-chloro-4-methylpentan-2-one. ¹H NMR (d₆-DMSO) δ 10.89 (bs, 1H), 8.15(s, 1H), 7.43 (t, 2H), 7.31 (s, 1H), 7.20 (t, 1H), 7.11 (d, 2H), 6.61(s, 1H), 2.42 (d, 2H), 1.98 (m, 1H), 0.88 (d, 6H); Mass spectrum (esi)m/z=360 (100), 362 (37).

Example 21 4-Butyl-N-(5-chloro-3-phenoxypyridin-2-yl)thiazol-2-amine

Prepared according to the method of Example 7, using1-chlorohexan-2-one. ¹H NMR (d₆-DMSO) δ 10.89 (bs, 1H), 8.15 (s, 1H),7.42 (t, 2H), 7.32 (s, 1H), 7.21 (t, 1H), 7.10 (d, 2H), 6.61 (s, 1H),2.56 (t, 2H), 1.59 (m, 2H), 1.31 (m, 2H), 0.87 (t, 3H); Mass spectrum(esi) m/z=360 (100), 362 (37).

Example 22N-(5-chloro-3-phenoxypyridin-2-yl)-4-cyclopropylthiazol-2-amine

Prepared according to the method of Example 7, using2-bromo-1-cyclopropylethanone. ¹H NMR (d₆-DMSO) δ 10.82 (bs, 1H), 8.15(s, 1H), 7.43 (t, 2H), 7.31 (s, 1H), 7.21 (t, 1H), 7.10 (d, 2H), 6.64(s, 1H), 1.94 (m, 1H), 0.72-0.85 (m, 4H); Mass spectrum (esi) m/z=344(100), 346 (37).

Example 235-(2-Methoxybenzylthio)-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-aminehydrochloride

Prepared according to the method of Example 16 with1-(chloromethyl)-2-methoxybenzene. ¹H NMR (d₆-DMSO) 8.8.05 (d, 1H), 7.43(t, 2H), 7.21 (q, 2H), 7.11 (d, 1H), 7.01 (m, 3H), 6.93 (d, 1H), 6.80(t, 1H), 6.69 (s, 1H), 4.01 (s, 2H), 3.68 (s, 3H), 2.26 (s, 3H); Massspectrum (apci) m/z=436.2 (M+H—HCl).

Example 245-(4-Methoxybenzylthio-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-aminehydrochloride

Prepared according to the method of Example 16 with1-(chloromethyl)-4-methoxybenzene. ¹H NMR (d₆-DMSO) δ 8.09 (d, 1H), 7.42(t, 2H), 7.21 (t, 1H), 7.14 (d, 1H), 7.10 (d, 2H), 7.00 (d, 2H), 6.81(d, 2H), 6.75 (s, 1H), 4.06 (s, 2H), 3.71 (s, 3H), 2.27 (s, 3H); Massspectrum (apci) m/z=436.2 (M+H—HCl).

Example 255-(2-Chlorobenzylthio)-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-aminehydrochloride

Prepared according to the method of Example 16, with1-(bromomethyl)-2-chlorobenzene (0.0512 g, 0.249 mmol) were reacted toprovide5-(2-chlorobenzylthio)-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-aminehydrochloride (0.073 g, 61.5%) after HCl salt formation. ¹H NMR(d₆-DMSO) δ 8.09 (d, 1H), 7.42 (m, 3H), 7.27 (dt, 1H), 7.18 (m, 3H),7.08 (d, 1H), 7.00 (d, 2H), 6.71 (s, 1H), 4.15 (s, 2H), 2.26 (s, 3H);Mass spectrum (apci) m/z=440.1 (M+H—HCl).

Example 26 Representative ExampleN-(4-Methylthiazol-2-yl)-3-phenoxy-5-(1-phenylethylthio)pyridin-2-aminehydrochloride

Prepared according to the method of Example 16 with1-(1-bromoethyl)benzene (0.0461 g, 0.249 mmol) were reacted to provideN-(4-methylthiazol-2-yl)-3-phenoxy-5-(1-phenylethylthio)pyridin-2-aminehydrochloride (0.058 g, 51.1%). ¹H NMR (d₆-DMSO) δ 8.05 (d, 1H), 7.42(t, 2H), 7.22 (m, 6H), 7.03 (d, 1H), 6.94 (d, 2H), 6.73 (s, 1H), 4.43(q, 1H), 2.26 (s, 3H), 1.51 (d, 3H); Mass spectrum (apci) m/z=420.1(M+H—HCl).

Example 27 N-(4-methylthiazol-2-yl)-3-(phenylthio)pyridin-2-aminehydrochloride

Prepared according to the method of Example 13 with3-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine and benzenethiol. ¹H NMR(d₆-DMSO) 8.42 (m, 1H), 7.90 (m, 1H), 7.41-7.25 (m, 5H), 7.12 (m, 1H),6.74 (m, 1H), 2.25 (s, 3H); Mass spectrum (esi) m/z=300.2(100)(M+H—HCl).

Example 283-(2-Chlorophenylthio)-N-(4-methylthiazol-2-yl)pyridin-2-aminehydrochloride

Prepared according to the method of Example 13, with3-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine and2-chlorobenzenethiol. ¹H NMR (d₆-DMSO) δ 8.45 (m, 1H), 7.80 (bs, 1H),7.57 (m, 1H), 7.27 (m, 2H), 7.07 (m, 1H), 6.84 (m, 1H), 6.62 (m, 1H),2.21 (s, 3H); Mass spectrum (esi) m/z=334.2 (100)(M+H—HCl).

Example 293-(3-Methoxyphenylthio)-N-(4-methylthiazol-2-yl)pyridin-2-aminehydrochloride

Prepared according to the method of Example 13, with3-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine and3-methoxybenzenethiol. ¹H NMR (d₆-DMSO) δ 8.43 (d, 1H), 7.92 (bs, 1H),7.27 (m, 1H), 7.12 (m, 1H), 6.86 (m, 2H), 6.80 (d, 1H), 6.72 (s, 1H),3.72 (s, 3H), 2.25 (s, 3H).

Example 30 Methyl2-(2-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)benzoate hydrochloride

Prepared according to the method of Example 13, with3-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine and methyl2-mercaptobenzoate. ¹H NMR (d₆-DMSO) δ 8.54 (d, 1H), 8.07 (s, 1H), 8.01(dd, 1H), 7.41 (m, 1H), 7.28 (m, 1H), 7.19 (m, 1H), 6.73 (m, 1H), 6.61(d, 1H), 3.92 (s, 3H), 2.21 (s, 3H).

Example 31 3-(Cyclopentylthio)-N-(4-methylthiazol-2-yl)pyridin-2-aminehydrochloride

Prepared according to the method of Example 13, with3-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine and cyclopentanethiol.¹H NMR (d₆-DMSO) δ 8.39 (d, 1H), 8.05 (d, 1H), 7.18 (dd, 1H), 6.89 (s,1H), 3.64 (m, 1H), 2.33 (s, 3H), 1.95 (m, 2H), 1.75 (m, 2H), 1.53 (m,4H); Mass spectrum (esi) m/z=292.1 (100)(M+H—HCl).

Example 32 N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-aminehydrochloride

Prepared according to the method of Example 8, using5-bromo-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine. ¹H NMR(d₆-DMSO) δ 8.20 (d, 1H), 7.46 (t, 2H), 7.39 (d, 1H), 7.24 (t, 1H), 7.15(m, 3H), 6.89 (s, 1H), 2.33 (s, 3H); Mass spectrum (apci) m/z=284.2(M+H—HCl).

Example 33N-(4-methylthiazol-2-yl)-3-phenoxy-5-(1-(pyridin-2-yl)ethylthio)pyridin-2-aminedihydrochloride

Step A: Preparation of 2-(1-bromoethyl)pyridine: 2-Ethylpyridine (20.0g, 186.65 mmol) was placed in carbon tetrachloride (830 mL) and benzoylperoxide (4.5211 g, 18.665 mmol) and 1-bromopyrrolidine-2,5-dione(33.221 g, 186.65 mmol) were added. The reaction mixture was heated toreflux for 18 hours, then cooled to room temperature and filtered. Thefiltrate was concentrated and the residue was purified over a plug ofsilica to give 2-(1-bromoethyl)pyridine (17.312 g, 49.9%). ¹H NMR(CDCl₃) δ 8.58 (d, 1H), 7.69 (td, 1H), 7.76 (d, 1H), 7.20 (dd, 1H), 5.24(q, 1H), 2.08 (d, 3H)

Step B: Preparation ofN-(4-methylthiazol-2-yl-3-phenoxy-5-(1-(pyridin-2-yl)ethylthio)pyridin-2-aminedihydrochloride: Following the procedure in Example 16, methyl3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate(0.325 g, 0.809 mmol), 1M potassium 2-methylpropan-2-olate (2.83 mL,2.83 mmol), and 2-(1-bromoethyl)pyridine (0.151 g, 0.809 mmol) werereacted to provideN-(4-methylthiazol-2-yl)-3-phenoxy-5-(1-(pyridin-2-yl)ethylthio)pyridin-2-aminehydrochloride (0.114 g, 30.8%) after reverse phase purification and HClsalt formation. ¹H NMR (d₆-DMSO) δ 8.58 (d, 1H), 8.09 (m, 1H), 8.04 (d,1H), 7.58 (d, 2H), 7.45 (t, 2H), 7.23 (t, 1H), 7.02 (d, 2H), 6.95 (d,1H), 6.79 (s, 1H), 4.67 (q, 1H), 2.28 (s, 3H), 1.62 (d, 3H); Massspectrum (esi) m/z=421.1 (M+H-2HCl).

Example 345-(3-Methoxybenzylthio)-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-aminehydrochloride

Prepared according to the method of Example 16, using methyl3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoateand 1-(chloromethyl)-3-methoxybenzene. ¹H NMR (d₆-DMSO) δ 8.09 (d, 1H),7.42 (t, 2H), 7.18 (m, 3H), 6.98 (d, 2H), 6:76 (m, 4H), 4.09 (s, 2H),3.68 (s, 3H), 2.26 (s, 3H); Mass spectrum (esi) m/z=436.2 (M+H-1HCl).

Example 353-(Cyclohex-2-enyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine

2-(4-Methylthiazol-2-ylamino)pyridin-3-ol (0.250 g, 1.21 mmol) andCs₂CO₃ (1.18 g, 3.62 mmol) were added to DMF (3 mL).3-Bromocyclohex-1-ene (0.216 g, 1.21 mmol) was added, and the reactionmixture was stirred for 3 hours. Water was added and the reactionmixture was extracted with ether. The organic layer was dried, filtered,and concentrated. The residue was purified by silica gel chromatographyprovide 3-(cyclohex-2-enyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine(0.130 g=37.5%). ¹H NMR (d₆-DMSO) δ 9.53 (s, 1H), 7.85 (dd, 1H), 7.41(d, 1H), 6.90 (dd, 1H), 6.58 (s, 1H), 6.00 (m, 1H), 6.88 (m, 1H), 6.88(m, 1H), 4.99 (m, 1H), 2.24 (s, 3H), 2.05 (m, 2H), 1.87 (m, 3H), 1.62(m, 1H); Mass spectrum (apci) m/z=288.0 (M+H).

Example 36 Representative Example

3-(Cyclohexyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride

3-(Cyclohex-2-enyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.115 g,0.400 mmol) and 4-methylbenzenesulfonohydrazide (1.12 g, 6.00 mmol) wereplaced in dimethoxyethane (5 mL). NaOAc (0.492 g, 6.00 mmol) wasdissolved in water (2 mL) and added to the above solution and refluxed.Additional 4-methylbenzenesulfonohydrazide (1.12 g, 6.00 mmol) was addedand the reaction mixture was refluxed overnight. An aqueous work up wasdone and the crude material was purified by silica gel chromatography toprovide 3-(cyclohexyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.064g, 55.3%) after HCl salt formation. ¹H NMR (d₆-DMSO) δ 7.79 (d, 1H),7.57 (d, 1H), 7.09 (m, 1H), 6.83 (s, 1H), 4.54 (m, 1H), 2.32 (s, 3H),1.97 (m, 2H), 1.79, (m, 2H), 1.57 (m, 3H), 1.36 (m, 3H); Mass spectrum(apci) m/z=291.1 (M+H—HCl).

Example 37 3-(Cyclopentyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-aminehydrochloride

Prepared according to the method of Example 35 with iodocyclopentane. ¹HNMR (d₆-DMSO) δ 7.92 (d, 1H), 7.46 (d, 1H), 7.08 (dd, 1H), 6.80 (s, 1H),5.49 (m, 1H), 2.32 (s, 3H), 1.88 (m, 6H), 1.60 (m, 2H); Mass spectrum(apci) m/z=276.1 (M+H—HCl).

Example 385-(3-(Dimethylamino)propylthio)-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-aminedihydrochloride

Prepared according to Example 16 from methyl3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoateand potassium 2-methylpropan-2-olate, with the exception that thereaction mixture was heated to 50° C. for 30 minutes. ¹H NMR (d₆-DMSO) δ9.90 (s, 1H), 8.21 (d, 1H), 7.43 (t, 2H), 7.39 (d, 1H), 7.18 (t, 1H),7.08 (d, 2H), 6.67 (s, 1H), 3.10 (m, 2H), 2.92 (t, 2H), 2.72 (d, 6H),2.24 (s, 3H), 1.85 (m, 2H); Mass spectrum (apci) m/z=401.2 (M+H-2HCl).

Example 39 Representative Example

Ethyl3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)-4-chlorobenzoate

Step A: Preparation of 3-(5-bromo-2-chlorophenoxy)pyridin-2-amine:4-2-aminopyridin-3-ol (7.56 g, 68.6 mmol) was added to a mixture ofsodium hydride (1.72 g, 71.9 mmol) in DMF (20 mL) and stirred for 10minutes. 4-Bromo-1-chloro-2-fluorobenzene (13.69 g, 65.4 mmol) was addedand the reaction mixture was stirred at 100° C. for 38 hours. Thereaction mixture was cooled to room temperature and partition between 1NNaOH and ether. The organic layer was dried over sodium sulfate,filtered, and concentrated. The residue was triturated with hexanes togive 3-(5-bromo-2-chlorophenoxy)pyridin-2-amine (11.30 g, 57.7%) as ayellow solid.

Step B: Preparation of ethyl3-(2-aminopyridin-3-yloxy)-4-chlorobenzoate:3-(5-Bromo-2-chlorophenoxy)pyridin-2-amine (11.30 g, 37.72 mmol),triethylamine (3.817 g, 37.72 mmol), Pd(OAc)₂ (0.8469 g, 3.772 mmol),and triphenylphosphine (0.9894 g, 3.772 mmol) were added to ethanol (100mL) in a bomb. The bomb was pressurized with 100 psi CO and heated to100° C. for 4 hours. The reaction mixture was cooled to room temperatureand filtered. Dichloromethane was added and solids were filtered off.The filtrate was washed with water. The organic layer was dried oversodium sulfate, filtered, and concentrated. The residue was purified bysilica gel chromatography to give ethyl3-(2-aminopyridin-3-yloxy)-4-chlorobenzoate (7.555 g, 68.42%).

Step C: Preparation of ethyl3-(2-amino-5-bromopyridin-3-yloxy)-4-chlorobenzoate: Prepared accordingto the method of Example 10, Step B.

Step D: Preparation of ethyl3-(2-(3-benzoylthioureido)-5-bromopyridin-3-yloxy)-4-chlorobenzoate:Ethyl 3-(2-amino-5-bromopyridin-3-yloxy)-4-chlorobenzoate (9.645 g,25.95 mmol) and benzoyl isothiocyanate (4.659 g, 28.55 mmol) were placedin THF (250 mL) and the reaction mixture was stirred at room temperaturefor 18 hours, then heated at 55° C. for two days. THF was removed andthe residue was purified by silica gel chromatography (5-25% EtOAc inhexane) to provide ethyl3-(2-(3-benzoylthioureido)-5-bromopyridin-3-yloxy)-4-chlorobenzoate(7.08 g, 51.0%) as a yellow solid.

Step E: Preparation of ethyl3-(5-bromo-2-thioureidopyridin-3-yloxy)-4-chlorobenzoate: Ethyl3-(2-(3-benzoylthioureido)-5-bromopyridin-3-yloxy)-4-chlorobenzoate(8.05 g, 15.1 mmol) and K₂CO₃ (10.4 g, 75.3 mmol) were placed in ethanol(150 mL) and heated to reflux for 2 days and then cooled. The reactionmixture was filtered and the filtrate was concentrated, triturated withwater, and dried. The remaining solid was dissolved in CH₂Cl₂ andpurified by silica gel chromatography to give ethyl3-(5-bromo-2-thioureidopyridin-3-yloxy)-4-chlorobenzoate (1.70 g, 26.2%yield).

Step F: Ethyl 3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-voxy)-4-chlorobenzoate: 1-chloropropan-2-one (0.469 g, 5.07 mmol), ethyl3-(5-bromo-2-thioureidopyridin-3-yloxy)-4-chlorobenzoate (1.680 g, 3.39mmol), triethylamine (0.671 g, 6.63 mmol), and ethanol (70 mL) werereacted according to the method of Example 10, Step E, to provide thetitle compound (1.40 g, 77% yield). ¹H NMR (d₆-DMSO) δ 8.26 (d, 1H),7.78 (m, 2H), 7.50 (s, 1H), 7.46 (d, 1H), 6.59 (s, 1H), 4.29 (q, 2H),2.23 (s, 3H), 1.28 (t, 3H); Mass spectrum (apci) m/z=470.1 (M+H).

Example 40N-(5-Bromo-3-(phenylthio)pyridin-2-yl)-4-methylthiazol-2-amine

Step A: Preparation of 3-(phenylthio)pyridin-2-amine: A mixture of3-bromopyridin-2-amine (167 mg, 0.966 mmol), Pd₂dba₃ (22.1 mg, 0.024mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (27.9 mg,0.048 mmol), N-ethyl-N-isopropylpropan-2-amine (0.33 mL, 1.9 mmol),thiophenol (121 mg, 1.1 mmol), and dioxane (10 mL) was heated at 100° C.under nitrogen for 2 hours. The reaction mixture was cooled to roomtemperature, filtered and concentrated. The reaction mixture waspurified by MPLC to afford 3-(phenylthio)pyridin-2-amine.

Step B: Preparation of 5-bromo-3-(phenylthio)pyridin-2-amine: Preparedaccording to the method of Example 10, Step B.

Steps C-E:N-(5-bromo-3-(phenylthio)pyridin-2-yl)-4-methylthiazol-2-amine: Preparedaccording to the method of Example 7 Steps C-E. ¹H NMR (CDCl₃) δ 9.01(s, 1H), 8.42 (m, 1H), 7.92 (m, 1H), 7.32-7.15 (m, 5H), 6.44 (m, 1H0,2.32 (m, 3H). Mass spectrum (apci) m/z=379.8 (M+H).

Example 41 Representative Example Preparation of6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ol

N-(5-Bromo-3-phenoxypyridin-2-yl)-4-methylthiazol-2-amine (2.66 mmol) isdissolved in THF (30 mL) and cooled to −78° C. MeLi (2.07 mL, 3.32 mmol)is slowly added and the reaction mixture is stirred for 10 minutes.n-Butyllithium (1.33 mL, 3.32 mmol) is added and the reaction mixture isstirred for 15 minutes. Triisopropylborate (0.613 mL, 2.66 mmol) isadded and the reaction mixture is stirred for 30 minutes. The reactionmixture is warmed to 0° C., and methanol (5 mL), 10% aqueous NaOH (5.1mL, 12.8 mmol), and 30% aqueous H₂O₂ (1.27 mL, 13.3 mmol) are added. Thereaction mixture is stirred at 0° C. for 1 hour, then purified by silicagel chromatography (10-20% EtOAc in hexanes) to afford6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ol.

Example 42 Preparation of5-(2-chlorophenylthio)-6-(4-methylthiazol-2-ylamino)pyridin-3-ol

A degassed mixture ofN-(5-bromo-3-(2-chlorophenylthio)pyridin-2-yl)-4-methylthiazol-2-amine(1.10 g, 2.66 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.35 g,5.32 mmol), Pd(OAc)₂ (60 mg, 0.27 mmol), tricyclopentylphosphine (93 mg.0.40 mmol) and cesium fluoride (3.64 g, 23.9 mmol) in acetonitrile isheated at 90° C. for 5 hours. The reaction mixture is cooled andpartitioned between ether and water. The crude product is dissolved inTHF. N-morpholine N-oxide (1.40 g, 12.0 mmol) is added and the reactionmixture is heated at reflux for 12 hours. The reaction mixture is cooledand partitioned between ether and water: The organic layer is washedwith water and brine, dried and concentrated. The residue is purified bysilica gel chromatography, eluting with 10-20% EtOAc in hexanes toafford the title compound.

Example 43 Preparation ofN-(5-methoxy-3-phenoxypyridin-2-yl)-4-methylthiazol-2-amine

Iodomethane (0.0362 g, 0.255 mmol) is added to a mixture of6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ol (0.255 mmol) andpotassium carbonate (0.0794 g, 0.574 mmol) in DMF (3 mL) and stirredovernight at room temperature. The reaction mixture is partitionedbetween water and ether. The organic layer is washed with water, dried,and concentrated. The residue is purified by silica gel chromatography,eluting with 15-20% EtOAc in hexanes, to afford the title compound.

Example 44 Preparation of methyl3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-yl)propanoate

Step A: N-(5-bromo-3-phenoxypyridin-2-yl)-4-methylthiazol-2-amine (724mg, 2.00 mmol) was dissolved in THF (20 mL) and cooled to −78° C. MeLi(1.30 mL, 2.20 mmol) is added slowly, and stirred for 10 minutes.n-Butyllithium (0.88 mL, 2.20 mmol) was added and the reaction mixturewas stirred for 15 minutes. DMF (0.31 mL, 4.00 mmol) was added, and thereaction mixture was stirred for 30 minutes. The reaction mixture waswarmed to room temperature and AcOH (2 mL) is added. The reactionmixture was stirred at room temperature for 1 hour, poured intosaturated aqueous sodium bicarbonate and extracted with ethyl acetate.The combined organic layers were dried over sodium sulfate, filtered andconcentrated. The residue was purified by silica gel (10-20% EtOAc inhexanes) to afford6-(4-methylthiazol-2-ylamino)-5-phenoxynicotinaldehyd.

Step B: Step B: To a mixture of mL6-(4-methylthiazol-2-ylamino)-5-phenoxynicotinaldehyde (311 mg, 1.00mmol) and THF (10 mL) was addedmethyl(triphenylphosphoranylidene)acetate (500 mg, 1.5 mmol) and thereaction mixture was stirred at room temperature. After 4 hours,additional methyl(triphenylphosphoranylidene)acetate (500 mg, 1.5 mmol)was added and the reaction mixture was stirred overnight. Filtered,concentrated the filtrate, and purified by silica gel chromatography(1:1 EtOAc in hexanes) to afford (E)-methyl3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-yl)acrylate.

Step C: A mixture of mL (E)-methyl3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-yl)acrylate (500 mg,1.36 mmol), 4-methylbenzenesulfonohydrazide (1.27 g, 6.8 mmol), andtoluene (15 mL) was heated at reflux for 12 hours, cooled to roomtemperature and concentrated. The residue was purified by silica gel (20to 30% EtOAc in hexanes) to afford the title compound.

Example 45 Preparation of3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-yl)propanoic acidhydrochloride

A mixture of mL methyl3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-yl)propanoate (1.50mmol) and ethanol (30 mL) and 1M NaOH (10 mL) was stirred and heated at60° C. for 3 hours. Concentrated and water and 6N HCl (2 mL) were added.Filtered and dried to yield the title compound.

Example 46 3-Benzyl-N-(4-methylthiazol-2-yl)pyridin-2-aminehydrochloride

A mixture of mL 3-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (70 mg,0.26 mmol), Cs₂CO₃ (250 mg, 0.78 mmol), PdCl₂ (dppf) (21.2 mg, 0.026mmol), and DMF (2 mL) and water (0.5 mL) was purged with nitrogen and9-benzyl-9-bora-bicyclo[3.3.1]nonane (1.5 mL, 0.78 mmol) was added andheated to 60° C. overnight. Additional9-benzyl-9-bora-bicyclo[3.3.1]nonane (1.5 mL, 0.78 mmol) was added andheated again overnight. Poured into water and extracted with ether. Theorganic layer was dried with sodium sulfate, filtered and concentrated.The residue was purified on silica gel (10% EtOAc in hexanes) to affordthe title compound (41.7 mg, 50.6% yield) as a white solid after HClsalt formation. ¹H NMR (d₆-DMSO) δ 8.30 (d, 1H), 7.62 (d, 1H), 7.35-7.10(m, 6H), 6.82 (s, 1H), 4.21 (s, 2H), 2.32 (s, 3H); Mass spectrum (esi)m/z=282.2 (100)(M+H—HCl).

Example 47 Preparation ofN-(5-bromo-3-(2-chlorophenylthio)pyridin-2-yl)-4-methylthiazol-2-amine

Prepared according to the method of Example 40. ¹H NMR (CDCl₃) δ 8.95(bs, 1H), 8.49 (d, 1h), 7.95 (d, 1h), 7.41 (dd, 1H), 7.19-7.08 (m, 2H),6.69 (dd, 1H), 6.45 (s, 1H), 2.32 (s, 3H); Mass spectrum (esi) m/z=414.1(M+H).

Example 48N-(3-(2-chlorophenylthio)-5-(phenylthio)pyridin-2-yl)-4-methylthiazol-2-aminehydrochloride

Prepared according to the method of Example 13 fromN-(5-bromo-3-(2-chlorophenylthio)pyridin-2-yl)-4-methylthiazol-2-amine(prepared according to Example 47) and benzenethiol. ¹H NMR (d₆-DMSO) δ8.36 (bs, 1H), 7.57 (dd, 1H), 7.40-7.15 (m, 100H), 6.54 (s, 1H), 2.20(s, 3H); Mass spectrum (esi) m/z=442.2 (M+H—HCl).

Example 49 Methyl3-(5-(2-chlorophenylthio)-6-(4-methylthiazol-2-2-ylamino)pyridin-3-ylthio)propanoate

Prepared according to the method of Example 13 fromN-(5-bromo-3-(2-chlorophenylthio)pyridin-2-yl)-4-methylthiazol-2-amine(prepared according to Example 47) and methyl 3-mercaptopropanoate. ¹HNMR (CDCl₃) δ 9.01 (bs, 1H), 8.52 (d, 1H), 7.95 (d, 1H), 7.40 (dd, 1H),7.16-7.06 (m, 2H), 6.66 (dd, 1H), 6.46 (s, 1H), 3.68 (s, 3H), 3.07 (t,2H), 2.61 (t, 2H), 2.32 (s, 3H).; Mass spectrum (esi) m/z=452.1 (M+H).

Example 50N-(3-(2-chlorophenylthio)-5-(1-(pyridin-2-yl)ethylthio)pyridin-2-yl)-4-methylthiazol-2-aminedihydrochloride

Prepared according to the method of Example 16 from methyl3-(5-(2-chlorophenylthio)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate(prepared according to Example 49), and 2-(1-bromoethyl)pyridine. ¹H NMR(d₆-DMSO) δ 8.54 (d, 1H), 8.19 (bs, 1H), 7.97 (m, 1H), 7.61 (dd, 1H),7.50 (m, 2H), 7.37 (m, 2H), 7.04 (bs, 2H), 6.52 (s, 1H), 4.56 (q, 1H),2.18 (s, 3H), 1.59 (d, 3H); Mass spectrum (esi) m/z=471.2 (M+H-2HCl).

Example 51N-3-(2-chlorophenylthio)-5-(piperidin-4-ylmethylthio)pyridin-2-yl)-4-methylthiazol-2-aminedihydrochloride

Prepared according to the method of Example 16 using methyl3-(5-(2-chlorophenylthio)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoateand tert-butyl 4-(bromomethyl)piperidine-1-carboxylate. ¹H NMR (d₆-DMSO)δ 12.15 (bs, 1H), 10.05 (bs, 1H), 8.64 (m, 1H), 8.32 (m, 2H), 7.63 (m,1H), 7.36 (m, 2H), 6.52 (s, 1H), 3.22 (m, 2H), 2.79 (m, 4H), 2.17 (s,3H), 1.86 (m, 2H), 1.61 (m, 1H), 1.36 (m, 2H); Mass spectrum (esi)m/z=463.0 (M+H-2HCl).

Example 52N-(3-(2-chlorophenylthio)-5-(3-(dimethylamino)propylthio)pyridin-2-yl)-4-methylthiazol-2-aminedihydrochloride

Prepared according to the method of Example 16 using methyl3-(5-(2-chlorophenylthio)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoateand 3-chloro-N,N-dimethylpropan-1-amine hydrochloride. ¹H NMR (d₆-DMSO)δ 10.12 (bs, 1H), 8.41 (s, 1H), 7.61 (d, 1H), 7.33 (m, 2H), 7.07 (m,1H), 6.52 (s, 1H), 3.09 (m, 2H), 2.90 (m, 2H), 2.70 (d, 6H), 2.18 (s,3H), 1.84 (m, 2H); Mass spectrum (esi) m/z=451.0 (M+H-2HCl).

Example 53N-(5-(2-chlorophenylthio)-3-phenoxypyridin-2-yl)-4-methylthiazol-2-aminehydrochloride

Prepared according to the method of Example 13, using5-bromo-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine and2-chlorobenzenethiol. ¹H NMR (d₆-DMSO) δ 8.26 (d, 1H), 7.49 (dd, 1H),7.42 (t, 2H), 7.29 (d, 1H), 7.27-7.12 (m, 4H), 6.96 (dd, 1H), 6.80 (s,1H), 2.30 (s, 3H); Mass spectrum (esi) m/z=426.4 (M+H—HCl).

Example 54N-(5-(3-chlorophenylthio)-3-phenoxypyridin-2-yl)-4-methylthiazol-2-aminehydrochloride

Prepared according to the method of Example 13, using3-chlorobenzenethiol. ¹H NMR (d₆-DMSO) δ 8.27 (d, 1H), 7.42 (t, 2h),7.35-7.10 (m, 8H), 6.81 (s, 1H), 2.30 (s, 3H); Mass spectrum (esi)m/z=426.3 (M+H—HCl).

Example 55N-(5-(2-methoxyphenylthio-3-phenoxypyridin-2-yl)-4-methylthiazol-2-aminehydrochloride

Prepared according to the method of Example 13, using2-methoxybenzenethiol. ¹H NMR (d₆-DMSO) δ 8.14 (d, 1H), 7.42 (t, 2H),7.27-7.18 (m, 2H), 7.13 (m, 2H), 7.02 (d, 1H), 6.98 (d, 1H), 6.89 (t,1H), 6.80 (s, 1H), 3.77 (s, 3H), 2.30 (s, 3H); Mass spectrum (esi)m/z=422.2 (M+H—HCl).

Example 56N-(5-(3-methoxyphenylthio)-3-phenoxypyridin-2-yl)-4-methylthiazol-2-aminehydrochloride

Prepared according to the method of Example 13, using3-methoxybenzenethiol. ¹H NMR (d₆-DMSO) δ 8.22 (s, 1H), 7.42 (m, 2H),7.27-7.18 (m, 3h), 7.14 (m, 2H), 6.86-6.77 (m, 4H), 3.71 (s, 3H), 2.31(s, 3H); Mass spectrum (esi) m/z=422.2 (M+H—HCl).

Example 573-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenol

A mixture ofN-(5-(3-methoxyphenylthio)-3-phenoxypyridin-2-yl)-4-methylthiazol-2-amine(prepared according to Example 56; 1.1 g, 2.6 mmol) and CH₂Cl₂ (20 mL)was cooled to 0° C. and tribromoborane (1M in CH₂Cl₂, 7.83 mL, 7.83mmol) was added and stirred at 0° C. for 1 hour. The reaction was slowlypoured into saturated aqueous sodium bicarbonate and extracted with 10%methanol in CH₂Cl₂. The organic layer was dried with sodium sulfate,filtered and concentrated. The residue was purified on silica gel (50 to80% EtOAc in hexanes) to afford3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenol (692mg, 65.1% yield) as a white solid. ¹H NMR (d₆-DMSO) δ 8.18 (dd, 1H),7.37 (m, 2H), 7.31 (d, 1H), 7.19 (m, 1H), 7.16 (dd, 1H), 7.11-7.02 (m,3H), 6.69-6.61 (m, 3H), 6.45 (m, 1H), 2.33 (s, 3H); Mass spectrum (esi)m/z=408.2 (M+H).

Example 582-3-6-4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenoxy)aceticacid hydrochloride

A mixture of3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenol(prepared according to Example 57; 200 mg, 0.491 mg), potassiumcarbonate (203 mg, 1.47 mmol), tert-butyl 2-bromoacetate (0.0725 mL,0.491 mmol), and DMF (4 mL) was stirred at room temperature for 30minutes. Water (15 mL) was added and the reaction mixture was extractedwith ether. The organic layer was dried with sodium sulfate, filteredand concentrated. The residue was purified on silica gel (10 to 15%EtOAc in hexanes) to afford the tert-butyl ester of the desiredmaterial. The material was dissolved in CH₂Cl₂ (3 mL) and 4N HCl indioxane added (4 mL) and stirred at room temperature overnight andconcentrated. The residue was dissolved in a small amount of CH₂Cl₂ andadded to vigorously stirred ether. The resultant precipitate wasfiltered to afford2-(3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenoxy)aceticacid hydrochloride (21.1 mg, 8.56% yield) as a white solid. ¹H NMR(d₆-DMSO) δ 9.70 (bs, 1H), 8.17 (d, 1H), 7.36 (t, 2H), 7.19 (d, 1H),7.15 (m, 2H), 6.99 (d, 2H), 6.71 (m, 2H), 6.65 (m, 3H), 4.86 (s, 2H),2.15 (s, 3H); Mass spectrum (esi) m/z=466.1 (M+H—HCl).

Example 594-methyl-N-(3-phenoxy-5-(3-(2-(piperidin-1-yl)ethoxy)phenylthio)pyridin-2-yl)thiazol-2-amine

A mixture of3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenol(prepared according to Example 57; 70.0 mg, 0.172 mmol), potassiumcarbonate (71.2 mg, 0.515 mmol), 1-(2-chloroethyl)piperidinehydrochloride (31.6 mg, 0.172 mmol), and DMF (2 mL) was stirred at roomtemperature for 30 minutes and heated to 50° C. overnight. The reactionwas cooled to room temperature and water (15 mL) was added and extractedwith ether. A white precipitate formed in the ether layer and wasfiltered to affordN-(4-methylthiazol-2-yl)-3-phenoxy-5-(3-(2-(piperidin-1-yl)ethoxy)phenylthio)pyridin-2-amine(34.2 mg, 38.4% yield) as a white solid. ¹H NMR (d₆-DMSO) δ 9.56 (s,1H), 8.29 (dd, 1H), 7.50 (dd, 1H), 7.28 (m, 2H), 7.11 (t, 1H), 7.00 (t,1H), 6.82 (m, 2H), 6.65 (m, 1H), 6.58 (m, 1H), 6.54 (m, 1H), 6.35 (m,1H), 3.79 (t, 2H), 2.23 (s, 3H), 2.17 (m, 4H), 2.12 (t, 2H), 1.38 (m,4H), 1.31 (m, 2H); Mass spectrum (esi) m/z=519.1 (M+H).

Example 60 N-(5-(3-(3-(dimethylamino)propoxy)phenylthio)-3-phenoxypyridin-2-yl)-4-methylthiazol-2-amine

Prepared according to the method of Example 60 using3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenol and3-chloro-N,N-dimethylpropan-1-amine hydrochloride. ¹H NMR (d₆-DMSO) δ9.55 (s, 1H), 8.28 (dd, 1H), 7.49 (dd, 1H), 7.29 (m, 2H), 7.11 (t, 1H),7.00 (t, 1H), 6.85 (m, 2H), 6.65 (m, 1H), 6.58 (m, 1H), 6.54 (m, 1H),6.38 (m, 1H), 3.70 (m, 2H), 2.21 (s, 3H), 2.04 (s, 6H) 1.96 (t, 2H),1.44 (m, 2H); Mass spectrum (esi) m/z=−493.1 (M+H).

Example 61 Representative Example tert-butyl3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)pyrrolidine-1-carboxylate

A mixture of5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-ol-hydrochloride (1.0 g,3.10 mmol), tert-butyl 3-bromopyrrolidine-1-carboxylate (WO 2003/062224)(1.01 g, 4.03 mmol), K₂CO₃ (1.29 g, 9.30 mmol), and DMF (20 mL) werereacted at 50° C. over the weekend. The reaction was cooled to roomtemperature, poured into water (250 mL) and extracted with EtOAc:ether(1:1). The organic layer was dried with sodium sulfate, filtered andconcentrated. The residue was purified on silica gel (40% EtOAc inhexanes) to afford tert-butyl3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)pyrrolidine-1-carboxylate(584 mg, 41.4% yield) as a tan solid. ¹H NMR (CDCl₃) δ 8.42 (bs, 1H),8.02 (s, 1 h), 7.10 (d, 1H), 6.42 (s, 1H), 4.95 (m, 1H), 3.75-3.44 (m,4H), 2.35 (d, 3H), 2.21 (m, 2H), 1.50 (s, 9H); Mass spectrum (apci)m/z=456.9 (M+H).

Example 62 Representative ExampleN-(5-bromo-3-(pyrrolidin-3-yloxy)pyridin-2-yl)-4-methylthiazol-2-aminedihydrochloride

A mixture of tert-butyl3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)pyrrolidine-1-carboxylate(prepared according to Example 61; 550 mg, 1.21 mmol) and CH₂Cl₂ (10 mL)and MeOH (2 mL) was stirred at room temperature. 4N HCl in dioxane (5mL) was added and the reaction mixture was stirred at room temperaturefor 30 minutes. The reaction was concentrated and dissolved in smallamount of CH₂Cl₂/methanol and added to vigorously stirred ether andfiltered to affordN-(5-bromo-3-(pyrrolidin-3-yloxy)pyridin-2-yl)-4-methylthiazol-2-aminedihydrochloride (478 mg, 92.4% yield) as a white solid. ¹H NMR (d₆-DMSO)δ 11.18 (bs, 1H), 9.80 (bs, 1H), 9.27 (bs, 1H), 8.09 (d, 1H), 7.83 (d,1H), 6.80 (s, 1H), 5.42 (m, 1H), 3.62-3.30 (m, 4H), 2.31 (s, 3H), 2.22(m, 2H); Mass spectrum (apci) m/z=357.0 (M+H-2HCl).

Example 631-(3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)pyrrolidin-1-yl)ethanonehydrochloride

A mixture ofN-(5-bromo-3-(pyrrolidin-3-yloxy)pyridin-2-yl)-4-methylthiazol-2-aminedihydrochloride (prepared according to Example 62; 70 mg, 0.16 mmol),triethylamine (0.11 mL, 0.82 mmol), and THF (2 mL) was stirred at roomtemperature. Acetyl chloride (0.009 mL, 0.16 mmol) was added and stirredat room temperature for 30 minutes. Water (15 mL) was added andextracted with EtOAc. The organic layer was dried with sodium sulfate,filtered and concentrated. The residue was purified on silica gel (10%methanol in EtOAc) to afford1-(3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)pyrrolidin-1-yl)ethanonehydrochloride (16 mg, 22.56% yield) as a white solid after HCl saltformation. ¹H NMR (d₆-DMSO) δ 11.60 (bs, 1H), 8.11 (m, 1H), 7.82 (m,1H), 6.90 (m, 1H), 5.28 (m, 1H), 3.81 (m, 1H), 3.59 (m, 3H), 2.33 (s,3H), 2.25 (m, 2H), 1.97 (m, 3H); Mass spectrum (apci) m/z=399.1(M+H—HCl).

Example 641-(3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)pyrrolidin-1-yl)-2-(dimethylamino)ethanonedihydrochloride

Prepared according to the method of Example 63, using2-(dimethylamino)acetyl chloride hydrochloride. ¹H NMR (d₆-DMSO) δ 11.13(bs, 1H), 9.75 (bs, 1H), 8.07 (d, 1H), 7.75 (m, 1H), 6.78 (s, 1H), 5.33(m, 1H), 4.25 (m, 2H), 4.10 (m, 1H), 3.71 (m, 4H), 2.83 (m, 6H), 2.29(m, 5H); Mass spectrum (apci) m/z=440.1 (M+H-2HCl).

Example 653-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)-N-isopropylpyrrolidine-1-carboxamide

Prepared according to the method of Example 63 using2-isocyanatopropane. ¹H NMR (d₆-DMSO) δ 10.49 (bs, 1H), 7.97 (m, 1H),7.52 (m, 1H), 6.61 (m, 1H), 5.82 (d, 1H), 5.17 (m, 1H), 3.75 (m, 1H),3.56 (m, 2H), 3.45 (m, 2H), 2.28-2.20 (m, 4H), 2.12 (m, 1H), 1.05 (m,6H); Mass spectrum (apci) m/z=440.1 (M+H).

Example 66N-(5-bromo-3-(1-(1-methyl-1H-imidazol-4-ylsulfonyl)pyrrolidin-3-yloxy)pyridin-2-yl)-4-methylthiazol-2-amine

Prepared according to the method of Example 63 using1-methyl-1H-imidazole-4-sulfonyl chloride. ¹H NMR (d₆-DMSO) δ 10:05 (bs,1H), 7.96 (d, 1H), 7.79 (s, 1H), 7.49 (m, 2H), 6.65 (s, 1H), 5.07 (m,1H), 3.63 (m, 2H), 3.55-3.40 (m, 5H), 2.28 (s, 3H), 2.19 (m, 1H), 2.02(m, 1H); Mass spectrum (apci) m/z=501.1 (M+H).

Example 675-(2-fluorobenzylthio)-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-aminehydrochloride

Prepared according to the method of Example 16 using1-(chloromethyl)-2-fluorobenzene. ¹H NMR (d₆-DMSO) δ 8.06 (d, 1H), 7.42(t, 2H), 7.28 (m, 1H), 7.15 (m, 4H), 7.09 (m, 1H), 6.97 (d, 2H), 6.69(s, 1H), 4.09 (s, 2H), 2.25 (s; 3H); Mass spectrum (esi) m/z=424.2 (100)(M+H—HCl).

Example 68N-(4-methylthiazol-2-yl)-3-phenoxy-5-(1-(pyridin-2-yl)propylthio)pyridin-2-aminedihydrochloride

Step A: Preparation of 2-(1-bromopropyl)pyridine: Prepared according tothe method of Example 33, Step A from 2-propylpyridine.

Step B: Preparation ofN-(4-methylthiazol-2-yl)-3-phenoxy-5-(1-(pyridin-2-yl)propylthio)pyridin-2-aminedihydrochloride: Prepared according to the method of Example 16. ¹H NMR(d₆-DMSO) δ 8.47 (s, 1H), 7.98 (d, 1H), 7.80 (m, 1H), 7.43 (t, 2H), 7.33(m, 2H), 7.20 (t, 1H), 6.95 (d, 2H), 6.92 (d, 1H), 6.65 (s, 1H), 4.26(t, 1H), 2.24 (s, 3H), 1.95 (m, 0.2H), 0.85 (t, 3H). Mass spectrum (esi)m/z=435.1 (100) (M+H-2HCl).

Example 692-((6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)methy)pyridin-3-oldihydrochloride

Prepared according to the method of Example 16 with2-(bromomethyl)pyridin-3-ol hydrobromide. ¹H NMR (d₆-DMSO) δ 8.16 (d,1H), 8.11 (d, 1H), 7.82 (m, 1H), 7.64 (m, 1H), 7.45 (t, 2H), 7.22 (t,1H), 7.08 (m, 3H), 6.76 (s, 1H), 4.26 (s, 2H), 2.28 (s, 3H); Massspectrum (esi) m/z=423.1 (100) (M+H-2HCl).

Example 703-(2-(3-phenoxy-5-(1-(pyridin-2-yl)ethylthio)pyridin-2-ylamino)thiazol-4-yl)propanoicacid dihydrochloride

Step A: Preparation of methyl 5-bromo-4-oxopentanoate: A solution ofbromine (27.71 g, 173.4 mmol) in methanol (40 mL) was added dropwise toa solution of ethyl 4-oxopentanoate (25.0 g, 173.4 mmol) in methanol(200 mL) at room temperature over a period of 30 minute, and thereaction mixture was stirred overnight. The reaction mixture wasconcentrated, and the residue was partitioned between 3:1 ether:ethylacetate and water, washed with saturated sodium bicarbonate, water,brine, dried, and concentrated to afford 17 g of a crude clear oil. Theoil was purified by MPLC (Biotage) eluting with 8:1 hexane ethyl acetateto afford methyl 5-bromo-4-oxopentanoate (10.65 g, 29.38% yield) as aclear oil. ¹H NMR (CDCl₃) δ 3.96 (s, 2H), 3.69 (s, 3H), 2.96 (t, 2H),2.66 (t, 2H).

Step B: Preparation of methyl3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoate:Prepared according to the method of Example 7, Step E, using1-(5-bromo-3-phenoxypyridin-2-yl)thiourea. ¹H NMR (d₆-DMSO) δ 10.95 (s,1H), 8.22 (d, 1H), 7.43 (t, 2H), 7.39 (s, 1H), 7.21 (t, 1H), 7.10 (d,2H), 6.68 (s, 1H), 3.59 (s, 3H), 2.84 (t, 2H), 2.68 (t, 2H); Massspectrum (esi) m/z=435.1 (100) (M+H).

Step C: Preparation of methyl3-(2-(5-(3-methoxy-3-oxopropylthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoate:Prepared according to the method of Example 13. ¹H NMR (d₆-DMSO) δ 10.87(s, 1H), 8.13 (d, 1H), 7.42 (t, 2H), 7.32 (d, 1H), 7.17 (t, 1H), 7.08(d, 2H), 6.67 (s, 1H), 3.59 (s, 3H), 3.55 (s, 3H), 3.03 (t, 2H), 2.84(t, 2H), 2.68 (t, 2H), 2.56 (t, 2H); Mass spectrum (esi) m/z=474.1 (100)(M+H).

Step D: Preparation of3-(2-(3-phenoxy-5-(1-(pyridin-2-yl)ethylthio)pyridin-2-ylamino)thiazol-4-yl)propanoicacid dihydrochloride: Prepared according to Example 16. The product wasfurther purified by reverse phase to give 106 mg of the t-Butyl ester.This was dissolved in CH₂Cl₂, and 4M HCl in dioxane was added and themixture was stirred at room temperature for 5 hours. The mixture wasconcentrated to give impure product. The product was dissolved in 1NNaOH and extracted with ether. The aqueous layer was acidified with 1MHCl and concentrated. The residue was dissolved in 10% MeOH in CH₂Cl₂,filtered, and concentrated. The residue was dissolved in 1N NaOH andextract with 10% EtOAc in Ether. The aqueous layer was acidified with 1MHCl and concentrated. The residue was dissolved in 10% MeOH in CH₂Cl₂,filtered and concentrated without the aid of heat to give3-(2-(3-phenoxy-5-(1-(pyridin-2-yl)ethylthio)pyridin-2-ylamino)thiazol-4-yl)propanoicacid dihydrochloride (0.027 g, 5.80% yield). ¹H NMR (d₆-DMSO) δ 8.41 (s,1H), 7.99 (s, 1H), 7.65 (t, 1H), 7.40 (t, 2H), 7.20 (m, 3H), 6.92 (m,3H), 6.50 (s, 1H), 4.42 (m, 1H), 2.70 (m, 2H), 2.29 (m, 2H), 1.54 (d,3H); Mass spectrum (esi) m/z=479.1 (100) (M+H-2HCl).

Example 714-chloro-3-(2-(4-methylthiazol-2-ylamino)-5-(phenylthio)pyridin-3-yloxy)benzoicacid hydrochloride

Step A: Preparation of ethyl4-chloro-3-(2-(4-methylthiazol-2-ylamino)-5-(phenylthio)pyridin-3-yloxy)benzoate:Prepared according to the method of Example 13, using Ethyl3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)-4-chlorobenzoateand benzenethiol.

Step B: Preparation of4-chloro-3-(2-(4-methylthiazol-2-ylamino)-5-(phenylthio)pyridin-3-yloxy)benzoicacid hydrochloride: Prepared according to the method of Example 45. ¹HNMR (d₆-DMSO) δ 8.26 (d, 1H), 7.71 (s, 2H), 7.41 (m, 1H), 7.30 (m, 3H),7.19 (m, 3H), 6.62 (s, 1H), 2.23 (s, 3H); Mass spectrum (esi) m/z=470.2(100) (M+H—HCl).

Example 724-chloro-N-(2-(dimethylamino)ethyl)-3-(2-(4-methylthiazol-2-ylamino)-5-(phenylthio)pyridin-3-yloxy)benzamidedihydrochloride

4-Chloro-3-(2-(4-methylthiazol-2-ylamino)-5-(phenylthio)pyridin-3-yloxy)benzoicacid (prepared according to Example 71; 0.131 g, 0.279 mmol) and TEA(0.117 mL, 0.836 mmol) were placed in a flask and cooled to 0° C. Ethylcarbonochloridate (0.0303 g, 0.279 mmol) was added, and the reactionmixture was stirred at 0° C. for 30 minutes.N1,N1-dimethylethane-1,2-diamine (0.0306 mL, 0.279 mmol) was added, andthe reaction mixture was stirred at room temperature for 1 hour. Waterwas added and the reaction mixture was extracted with CH₂Cl₂. Theorganic layer was concentrated and the residue was purified first bysilica gel chromatography and then by reverse phase chromatography toprovide the desired product as the free base. The free base wasdissolved in CH₂Cl₂ and HCl in ether was added to give4-chloro-N-(2-(dimethylamino)ethyl)-3-(2-(4-methylthiazol-2-ylamino)-5-(phenylthio)pyridin-3-yloxy)benzamidedihydrochloride (0.069 g, 40.4% yield). ¹H NMR (d₆-DMSO) δ 9.83 (bs,1H), 8.90 (m, 1H), 8.24 (m, 1H), 7.75 (m, 2H), 7.58 (s, 1H), 7.30 (m,2H), 7.19 (m, 4H), 6.67 (s, 1H), 3.59 (m, 2H), 3.23 (m, 2H), 2.80 (d,6H), 2.25 (s, 3H); Mass spectrum (esi) m/z=540.1 (100) (M+H-2HCl).

Example 734-chloro-3-(2-(4-methylthiazol-2-ylamino)-5-(1-(pyridin-2-pyridin-2-ethylthio)pyridin-3-yloxy)benzoicacid sodium salt

Step A: Preparation of ethyl4-chloro-3-(5-(3-methoxy-3-oxopropylthio)-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)benzoate:Prepared according to the method of Example 13 from ethyl3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)-4-chlorobenzoate.¹H NMR (d₆-DMSO) δ 11.12 (bs, 1H), 8.18 (d, 1H), 7.77 (s, 2H), 7.44 (s,1H), 7.35 (d, 1H), 6.61 (s, 1H), 4.47 (q, 2H), 3.54 (s, 3H), 3.04 (t,2H), 2.54 (t, 2H), 2.23 (s, 3H), 1.26 (t, 3H); Mass spectrum (esi)m/z=508.2 (100) (M+H).

Step B: Preparation of4-chloro-3-(2-(4-methylthiazol-2-ylamino)-5-(1-(pyridin-2-yl)ethylthio)pyridin-3-yloxy)benzoicacid sodium salt: Prepared according to the method of Example 16 using2-(1-bromoethyl)pyridine. ¹H NMR (d₆-DMSO) δ 8.49 (m, 1H), 8.04 (d, 1H),7.89 (m, 1H), 7.78 (m, 2H), 7.40 (m, 3H), 6.98 (d, 1H), 6.68 (s, 1H),4.60 (m, 1H), 2.25 (s, 3H), 1.58 (d, 3H); Mass spectrum (esi) m/z=499.1(100) (M+H—Na).

Example 744-chloro-N-(2-(dimethylamino)ethyl)-3-(2-(4-methylthiazol-2-ylamino)-5-(1-(pyridin-2-yl)ethylthiopyridin-3-yloxy)benzamidetrihydrochloride

4-chloro-3-(2-(4-methylthiazol-2-ylamino)-5-(1-(pyridin-2-yl)ethylthio)pyridin-3-yloxy)benzoicacid (prepared according to Example 73; 0.131 g, 0.263 mmol), TEA (d.0.726) (0.0732 mL, 0.525 mmol), ethyl-carbonochloridate (0.057 g, 0.525mmol), and N1,N1-dimethylethane-1,2-diamine (0.0231 g, 0.263 mmol) werereacted according the method of Example 72. 1N NaOH was added and thereaction mixture was stirred for 3 hours. The reaction mixture wasextracted with CH₂Cl₂. The combined extracts were concentrated andpurified by silica gel chromatography (4% MeOH in CH₂Cl₂, using 2% 7Nammonia in MeOH) and then purified by reverse phase chromatography togive the compound as the free base. The free base was dissolved inCH₂Cl₂ and HCl in ether was added. The mixture was concentrated to give4-chloro-N-(2-(dimethylamino)ethyl)-3-(2-(4-methylthiazol-2-ylamino)-5-(1-(pyridin-2-yl)ethylthio)pyridin-3-yloxy)benzamidetrihydrochloride (0.025 g, 14.8% yield). ¹H NMR (d₆-DMSO) δ 9.73 (s,1H), 8.91 (m, 1H), 8.42 (m, 1H), 8.01 (d, 1H), 7.78 (m, 3H), 7.51 (s,1H), 7.29 (m, 2H), 6.83 (s, 1H), 6.66 (m, 1H), 4.48 (q, 1H), 3.60 (m,2H), 3.24 (m, 2H), 2.81 (d, 6H), 2.24 (s, 3H), 1.54 (d, 3H); Massspectrum (esi) m/z=569.2 (100) (M+H-3HCl).

Following the procedure of Example 13, the following compounds were alsoprepared.

Example Structure Name Data 75

N-(3-(2,6- dichlorophenylthio) pyridin-2-yl)-4- methylthiazol-2-aminehydrochloride ¹H NMR (CDCl₃) δ 12.32 (bs, 1H), 8.25 (dd, 1H), 7.42 (d,2H), 7.38 (dd, 1H), 7.28 (dd, 1H), 6.98 (dd, 1H), 6.47 (s, 1H), 2.48 (s,3H). Mass spectrum (apci) m/z = 368.2 (M + H − HCl). 76

4-methyl-N-(3- (naphthalen-2- ylthio)pyridin-2- yl)thiazol-2-aminehydrochloride ¹H NMR (DMSO-d₆) δ 8.43 (d, 1H), 7.94-7.82 (m, 5H), 7.52(m, 2H), 7.39 (dd, 1H), 7.12 (m, 1H), 6.71 (s, 1H), 2.24 (s, 3H). Massspectrum (apci) m/z = 350.2 (M + H − HCl). 77

N-(5-(2- chlorophenylthio)-3- phenoxypyridin-2-yl)- 4-methylthiazol-2-amine hydrochloride ¹H NMR (DMSO-d₆) δ 8.26 (d, 1H), 7.49 (dd, 1H), 7.42(t, 2H), 7.29 (d, 1H), 7.25 (td, 2H), 7.19 (t, 1H), 7.15 (d, 2H), 6.96(dd, 1H), 6.80 (s, 1H), 2.30 (s, 3H). Mass spectrum (apci) m/z = 426.4(M + H − HCl). 78

N-(5-(3- chlorophenylthio)-3- phenoxypyridin-2-yl)- 4-methylthiazol-2-amine hydrochloride ¹H NMR (DMSO-d₆) δ 8.27 (d, 1H), 7.42 (t, 2H),7.35-7.11 (m, 8H), 6.81 (s, 1H), 2.30 (s, 3H). Mass spectrum (apci) m/z= 426.3 (M + H − HCl). 79

N-(5-(2- methoxyphenylthio)- 3-phenoxypyridin-2- yl)-4-methylthiazol-2-amine hydrochloride ¹H NMR (DMSO-d₆) δ 8.14 (d, 1H), 7.43 (t, 2H), 7.23(m, 2H), 7.13 (m, 3H), 7.02 (d, 1H), 6.98 (d, 1H), 6.89 (t, 1H), 6.80(s, 1H), 3.77 (s, 3H), 2.30 (s, 3H). Mass spectrum (apci) m/z = 422.2(M + H − HCl). 80

N-(5-(3- methoxyphenylthio)- 3-phenoxypyridin-2- yl)-4-methylthiazol-2-amino hydrochloride ¹H NMR (CDCl₃) δ 8.22 (d, 1H), 7.42 (m, 2H),7.27-7.19 (m, 3H), 7.14 (m, 2H), 3.71 (s, 3H), 2.31 (s, 3H). Massspectrum (apci) m/z = 422.2 (M + H − HCl). 81

methyl 3-(5-(2- chlorophenylthio)-6- (4-methylthiazol-2-ylamino)pyridin-3- ylthio)propanoate ¹H NMR (CDCl₃) δ 9.01 (s, 1H), 8.52(d, 1H), 7.95 (d, 1H), 7.40 (dd, 1H), 7.11 (m, 2H), 6.66 (dd, 1H), 6.46(s, 1H), 3.68 (s, 3H), 3.07 (t, 2H), 2.61 (t, 2H), 2.32 (s, 3H) Massspectrum (apci) m/z = 452.1 (M + H). 82

N-(5-(2,5- dimethoxyphenylthio)- 3-phenoxypyridin-2-yl)-4-methylthiazol-2- amine hydrochloride 1H NMR (DMSO-d6) δ 8.16 (d,1H), 7.42 (m, 2H), 7.20 (m, 2H), 7.11 (m, 2H), 6.95 (d, 1H), 6.79 (dd,1H), 6.75 (s, 1H), 6.44 (d, 1H), 3.72 (s, 3H), 3.61 (s, 3H), 2.28 (s,3H). Mass spectrum (apci) m/z = 452.2 (M + H − HCl). 83

N-(5-(2,5- dichlorophenylthio)-3- phenoxypyridin-2-yl)-4-methylthiazol-2- amine hydrochloride ¹H NMR (DMSO-d₆) δ 8.31 (d, 1H),7.52 (d, 1H), 7.40 (m, 3H), 7.28 (dd, 1H), 7.17 (d, 1H), 7.11 (d, 2H),6.84 (d, 1H), 6.71 (s, 1H), 2.27 (s, 3H). Mass spectrum (apci) m/z =460.2 (M + H − HCl). 84

N-(5-(2,5- dimethylphenylthio)- 3-phenoxypyridin-2-yl)-4-methylthiazol-2- amine hydrochloride ¹H NMR (DMSO-d₆) δ 8.08 (d,1H), 7.40 (t, 2H), 7.21-7.06 (m, 5H), 6.99 (d, 1H), 6.92 (s, 1H), 6.75(s, 1H), 2.28 (s, 3H). Mass spectrum (apci) m/z = 420.3 (M + H − HCl).85

N-(5-(1-(2- (dimethylamino)ethyl)- 1H-tetrazol-5-ylthio)-3-phenoxypyridin-2- yl)-4-methylthiazol-2- amine dihydrochloride ¹H NMR(DMSO-d₆) δ 10.62 (bs, 1H), 8.42 (d, 1H), 7.57 (d, 1H), 7.43 (t, 2H),7.20 (t, 1H), 7.11 (d, 2H), 6.74 (s, 1H), 4.85 (t, 2H), 3.65 (m, 2H),2.84 (s, 6H), 2.26 (s, 3H). Mass spectrum (apci) m/z = 455.0 (M + H −2HCl). 86

4-methyl-N-(5-(4- methyl-4H-1,2,4- triazol-3-ylthio)-3-phenoxypyridin-2- yl)thiazol-2-amine dihydrochloride ¹H NMR (DMSO-d₆) δ8.72 (s, 1H), 8.21 (dd, 1H), 7.42 (t, 2H), 7.30 (dd, 1H), 7.21 (t, 1H),7.08 (d, 2H), 6.71 (s, 1H), 3.62 (s, 3H), 2.25 (s, 3H). Mass spectrum(apci) m/z = 397.1 (M + H − 2HCl). 87

3-(2- chlorophenylthio)-N- (4-methylthiazol-2- yl)-5-(phenylthio)pyridin-2- amine hydrochloride ¹H NMR (DMSO-d₆) δ 8.35 (s,1H), 7.57 (dd, 1H), 7.40-7.15 (m, 9H), 6.54 (s, 1H), 2.20 (s, 3H). Massspectrum (apci) m/z = 442.2 (M + H − HCl). 88

N-(5- ([1,2,4]triazolo[4,3- a]pyridin-3-ylthio)-3- phenoxypyridin-2-yl)-4-methylthiazol-2- amine dihydrochloride ¹H NMR (DMSO-d₆) δ 11.00 (bs,1H), 8.59 (m, 1H), 8.27 (m, 1H), 7.87 (m, 1H), 7.50 (m, 1H), 7.37 (m,2H), 7.24 (m, 1H), 7.17 (m, 1H), 7.12 (m, 1H), 6.98 (d, 2H), 6.62 (s,1H), 2.21 (s, 3H). Mass spectrum (apci) m/z = 433.1 (M + H − 2HCl). 89

2-(4-methyl-5-(6-(4- methylthiazol-2- ylamino)-5- phenoxypyridin-3-ylthio)-4H-1,2,4- triazol-3- yl(acetonitrile dihydrochloride ¹H NMR(DMSO-d₆) δ 8.21 (t, 1H), 7.43 (m, 2H), 7.32 (t, 1H), 7.21 (t, 1h), 7.08(d, 2H), 6.72 (s, 1H), 4.37 (d, 2H), 3.55 (d, 3H), 2.26 (s, 3H). Massspectrum (apci) m/z = 436.2 (M + H − 2HCl). 90

methyl 3-(6-(4- phenethylthaizol-2- ylamino)-5- phenoxypyridin-3-ylthio)propanoate ¹H NMR (CDCl₃) δ 8.76 (bs, 1H), 8.16 (d, 1H), 7.42 (m,2H), 7.30-7.16 (m, 2H), 6.42 (s, 1H), 3.65 (s, 3H), 3.05-2.90 (m, 6H),2.26 (t, 2H). Mass spectrum (apci) m/z = 492.3 (M + H). 91

methyl 3-(6-(4-(1- methylpiperidin-4- yl)thiazol-2-ylamino)-5-phenoxypyridin-3- ylthio)propanoate dihydrochloride ¹H NMR (DMSO-d₆) δ10.92 (bs, 1H), 10.03 (bs, 1H), 8.15 (d, 1H), 7.43 (m, 2H), 7.33 (d,1H), 7.20 (m, 1H), 7.09 (m, 2H), 6.76 (s, 1H), 3.55 (s, 3H), 3.47 (m,2H), 3.04 (m, 4H), 2.81 (m, 1H), 2.75 (d, 3H), 2.56 (t, 2H), 2.15 (m,2H), 1.85 (m, 2H). Mass spectrum (apci) m/z = 485.3 (M + H − 2HCl). 92

methyl 3-(5-(4- fluorophenoxy)-6-(4- phenethylthiazol-2-ylamino)pyridin-3- ylthio)propanoate ¹H NMR (CDCl₃) δ 8.76 (bs, 1H),8.15 (d, 1H), 7.28 (m, 2H), 7.20 (m, 3H), 7.15-7.02 (m, 6H), 6.43 (s,1H), 3.65 (s, 3H), 3.05-2.92 (m, 6H), 2.56 (t, 2H). Mass spectrum (apci)m/z = 510.3 (M + H). 93

methyl 3-(5-(2- chlorophenylthio)-6- (4-methylthiazol-2-ylamino)pyridin-3- ylthio)propanoate ¹H NMR (CDCl₃) δ 9.01 (s, 1H), 8.52(d, 1H), 7.95 (d, 1H), 7.40 (dd, 1H), 7.11 (m, 2H), 6.66 (dd, 1H), 6.46(s, 1H), 3.68 (s, 3H), 3.08 (t 2H), 2.60 (t, 2H), 2.32 (s, 3H). Massspectrum (apci) m/z = 459.1 (M + H). 94

methyl 3-(6-(4- methylthiazol-2- ylamino)-5- (phenylthio)pyridin-3-ylthio)propanoate hydrochloride ¹H NMR (d₆-DMSO) δ 8.33 (s, 1H), 7.64(bs, 1H), 7.46-7.33 (m, 5H), 6.64 (s, 1H), 3.56 (s, 3H), 3.04 (t, 2H),2.54 (t, 2H), 2.23 (s, 3H). Mass spectrum (apci) m/z = 417.7 (M + H −HCl). 95

tert-butyl 4-(5-(3-(4- fluorophenoxy)-5-(3- methoxy-3-oxopropylthio)pyridin- 2-ylamino)-1,2,4- thiadiazol-3- yl)piperidine-1-carboxylate ¹H NMR (CDCl₃) δ 9.02 (s, 1H), 8.20 (m, lh), 7.13 (m, 3H),7.07 (m, 2H), 4.15 (m, 2H), 3.65 (s, 3H), 3.03 (t, 2H), 2.98 (m, 1h),2.90 (m, 2H), 2.57 (t, 2H), 2.04 (m, 2H), 1.81 (m, 2H), 1.46 (s, 9H).Mass spectrum (apci) m/z = 490.3 (M + H − Boc). 96

tert-butyl 4-((5-(3-(4- fluorophenoxy)-5-(3- methoxy-3-oxopropylthio)pyridin- 2-ylamino)-1,2,4- thiadiazol-3-yl)methyl)piperidine- 1-carboxylate ¹H NMR (CDCl₃) δ 9.01 (s, 1H), 8.20(d, 1H), 7.13 (m, 3H), 7.07 (m, 2H), 4.08 (m, 2H), 3.66 (s, 3H), 3.03(t, 2H), 2.78 (d, 2H), 2.71 (m, 2H), 2.57 (t, 2H), 2.05 (m, 1H), 1.68(m, 2H), 1.45 (s, 9H), 1.24 (m, 2H). Mass spectrum (apci) m/z = 504.3(M + H − Boc).

Following the procedure of Example 16, the following compounds were alsoprepared:

Ex- am- ple Structure Name Data  97

N-(3-(2-chlorophenylthio)-5-(1- (pyridin-2-yl)ethylthio)pyridin-2-yl)-4-methylthiazol-2-amine dihydrochloride ¹H NMR (DMSO-d₆) δ 8.54 (d,1H), 8.19 (s, 1H), 7.98 (t, 1H), 7.61 (dd, 1H), 7.51 (d, 1H), 7.47 (d,1H), 7.37 (m, 2H), 7.04 (bs, 2H), 6.52 (s, 1H), 4.56 (q, 1H), 2.18 (s,3H), 1.58 (d, 3H). Mass spectrum (apci) m/z = 471.2 (M + H − 2HCl).  98

N-(3-(2-chlorophenylthio)-5-(1- (piperidin-4-ylmethylthio)pyridin-2-yl)-4-methylthiazol-2-amine dihydrochloride ¹H NMR (DMSO-d₆) δ 12.20(bs, 1H), 10.05 (bs, 1H), 8.65 (d, 1H), 8.34 (m, 2H), 7.64 (d, 1H), 7.38(m, 2H), 3.22 (d, 2H), 2.79 (q, 4H), 2.17 (s, 3H), 1.86 (d, 2H), 1.61(m, 1H), 1.30 (m, 2H). Mass spectrum (apci) m/z = 463.0 (M + H − 2HCl). 99

N-(3-(2-chlorophenylthio)-5-(3- (dimethylamino)propylthio)pyridin-2-yl)-4-methylthiazol-2-amine dihydrochloride ¹H NMR (DMSO-d₆) δ 10.13(bs, 1H), 8.42 (s, 1H), 7.61 (d, 1H), 7.34 (m, 2H), 7.09 (m, 1H), 6.52(s, 1H), 3.09 (m, 2H), 2.91 (t, 2H), 2.70 (d, 6H), 2.19 (s, 3H), 1.84(m, 2H). Mass spectrum (apci) m/z = 451.1 (M + H − 2HCl). 100

4-phenethyl-N-(3-phenoxy-5- (piperidin-4-ylmethylthio)pyridin-2-yl)thiazol-2-amine dihydrochloride ¹H NMR (DMSO-d₆) δ 11.20 (bs, 1H),8.81 (m, 1H), 8.50 (m, 1H), 8.18 (d, 1H), 7.44 (m, 2H), 7.36 (d, 1H),7.30-7.15 (m, 6H), 7.10 (d, 2H), 6.71 (s, 1H), 3.22 (m, 2H), 2.98-2.73(m, 8H), 1.88 (m, 2H), 1.67 (m, 1H), 1.34 (m, 2H). Mass spectrum (apci)m/z = 503.2 (M + H − 2HCl).

Example 1013-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenol

Prepared according to the method of Example 57. ¹H NMR (CDCl₃) δ 8.18(dd, 1H), 7.38 (m, 2H), 7.31 (d, 1H), 7.19 (tq, 1H), 7.16 (dd, 1H),7.10-7.03 (m, 3H), 6.69-6.61 (m, 3H), 6.45 (t, 1H), 2.33 (s, 3H). MassSpectrum (apci): 408.2 (M+H).

Example 1024-methyl-N-(3-phenoxy-5-(3-(2-(piperidin-1-ylethoxy)phenylthio)pyridin-2-yl)thiazol-2-amine

Prepared according to the method of Example 59. ¹H NMR (d₆-DMSO) δ 9.56(s, 1H), 8.29 (dd, 1H), 7.50 (dd, 1H), 7.28 (m, 2H), 7.12 (t, 1H), 7.00(t, 1H), 6.83 (m, 2H), 6.65 (m, 1H), 6.58 (m, 1H), 6.54 (m, 1H), 6.35(s, 1H), 3.79 (t, 2H), 2.24 (s, 3H), 2.18 (m, 4H), 2.12 (t, 2H), 1.38(m, 4H), 1.31 (m, 2H). MS (apci): 519.1 (M+H).

Example 1032-(3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenoxy)aceticacid hydrochloride

Prepared according to the method of Example 58. ¹H NMR (d₆-DMSO)S 9.70(bs, 1H), 8.17 (d, 1H), 7.36 (t, 2H), 7.19 (d, 1H), 7.15 (m, 2H), 6.99(d, 2H), 6.71 (d, 1H), 6.66 (d, 1H), 6.63 (d, 2H), 4.86 (s, 2H), 2.15(s, 3H). Mass Spectrum (apci): 466.1 (M+H—HCl).

Example 104N-(5-(3-(3-(dimethylamino)propoxy)phenylthio)-3-phenoxypyridin-2-yl)-4-methylthiazol-2-amine

Prepared according to the method of Example 60. ¹H NMR (d₆-DMSO) δ 9.55(s, 1H), 8.28 (d, 1H), 7.49 (d, 1H), 7.29 (t, 2H), 7.11 (t, 1H), 7.00(t, 1H), 6.85 (d, 2H), 6.65 (d, 1H), 6.58 (dd, 1H), 6.54 (m, 1H), 6.38(s, 1H), 3.70 (m, 2H), 2.21 (s, 3H), 2.04 (s, 6H), 1.96 (t, 2H), 1.44(m, 2H). Mass Spectrum (apci): 493.1 (M+H).

Example 1051-(3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)pyrrolidin-yl)ethanonehydrochloride

Prepared according to the method of Example 63. ¹H NMR (d₆-DMSO) δ 11.55(bs, 1H), 8.11 (d, 1H), 7.81 (d, 1H), 6.90 (d, 1H), 5.28 (m, 1H),4.00-3.52 (m, 4H), 2.33 (s, 3H), 2.31-2.09 (m, 2H), 1.98 (d, 3H). Massspectrum (apci) m/z=399.1 (M+H—HCl).

Following the procedure of Example 105, Step H, the following compoundswere also prepared.

Example Structure Name Data 106

1-(3-(5-bromo-2-(4- methylthiazol-2- ylamino)pyridin-3-yloxy)pyrrolidin-1-yl)-2- (dimethylamino)ethanone dihydrochloride ¹H NMR(d₆-DMSO) δ 11.12 (bs, 1H), 9.75 (bs, 1H), 8.08 (d, 1H), 7.75 (d, 1H),6.78 (s, 1H), 5.32 (dt, 1H), 4.31-4.06 (m, 2H), 3.85-3.56 (m, 4H), 2.83(m, 6H), 2.40-2.10 (m, 5H). Mass spectrum (apci) m/z = 440.1 (M + H −2HCl). 107

4-(3-(5-bromo-2-(4- methylthiazol-2- ylamino)pyridin-3-yloxy)pyrrolidin-1-yl)-4- oxobutanoic acid ¹H NMR (d₆-DMSO) δ 12.20 (bs,1H), 11.65 (bs, 1H), 7.97 (m, 1H), 7.58 (m, 1H), 6.62 (m, 1H), 5.20 (dt,1H), 3.92-3.42 (m, 4H), 2.60-2.40 (m, 4H), 2.32-2.05 (m, 5H). Massspectrum (apci) m/z = 457.1 (M + H). 108

3-(5-bromo-2-(4- methylthiazol-2- ylamino)pyridin-3- yloxy)-N-isopropylpyrrolidine-1- carboxamide ¹H NMR (d₆-DMSO) δ 10.48 (bs, 1H),7.96 (m, 1H), 7.52 (m, 1H), 6.61 (m, 1H), 5.82 (d, 1H), 5.17 (m, 1H),3.75 (m, 1H), 3.61-3.42 (m, 4H), 2.28-2.05 (m, 5H), 1.05 (d, 6H). Massspectrum (apci) m/z = 440.1 (M + H). 109

N-(5-bromo-3-(1-(1- methyl-1H-imidazol-4- ylsulfonyl)pyrrolidin-3-yloxy)pyridin-2-yl)-4- methylthiazol-2-amine ¹H NMR (d₆-DMSO) δ 10.06(bs, 1H), 7.96 (d, 1H), 7.79 (s, 1H), 7.49 (m, 2H), 6.65 (s, 1H), 5.07(m, 1H), 3.69-3.39 (m, 7H), 2.28 (s, 3H), 2.20 (m, 1H), 2.03 (m, 1H).Mass spectrum (apci) m/z = 501.1 (M + H).

Example 110N-(5-bromo-3-(2-chlorophenylthio)pyridin-2-yl)-4-methylthiazol-2-amine

Prepared according to the method of Example 40. ¹H NMR (CDCl₃) δ 8.96(bs, 1H), 8.49 (d, 1H), 7.95 (d, 1H), 7.41 (dd, 1H), 7.13 (m, 2H), 6.69(dd, 1 h), 6.46 (s, 1H), 2.32 (s, 3H). Mass spectrum (apci) m/z=414.1(M+H).

The following compounds were prepared according to the method of Example7.

Example Structure Name Data 111

4-methyl-N-(3- phenoxy-5-(pyridin-2- ylthio)pyridin-2-yl)thiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ 8.39 (ddd, 1H),8.35 (dd, 1H), 7.70 (tdd, 1H), 7.45 (m, 3H), 7.20 (m, 5H), 6.92 (s, 1H),2.34 (s, 3H). Mass spectrum (apci) m/z = 393.2 (M + H − 2HCl). 112

4-methyl-N-(3- phenoxy-5-(pyridin-4- ylthio)pyridin-2-yl)thiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ 8.59 (d, 2H), 8.40(m, 1H), 7.68 (m, 1H), 7.66 (d, 1H), 7.51 (m, 1H), 7.43 (m, 2H), 7.19(m, 3H), 6.79 (s, 1H), 2.29 (s, 3H). Mass spectrum (apci) m/z = 393.2(M + H − 2HCl). 113

4-methyl-N-(3- phenoxy-5-(pyrimidin- 2-ylthio)pyridin-2-yl)thiazol-2-amine hydrochloride ¹H NMR (d₆-DMSO) δ 8.61 (m, 2H), 8.30(d, 1H), 7.48 (d, 1H), 7.43 (m, 2H), 7.25 (t, 1H), 7.17 (m, 3H), 6.75(s, 1H), 2.28 (s, 3H). Mass spectrum (apci) m/z = 394.2 (M + H − HCl).114

4-methyl-N-(5-(6- methylpyridin-2- ylthio)-3- phenoxypyridin-2-yl)thiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ 8.31 (d, 1h), 7.58(t, 1H), 7.43 (m, 3H), 7.20 (m, 3H), 7.04 (d, 1H), 6.89 (d, 1H), 6.82(s, 1H), 2.37 (s, 3H), 2.30 (s, 3H). Mass spectrum (apci) m/z = 407.2(M + H − 2HCl). 115

4-methyl-N-(5-(4- methylthiazol-2- ylthio)-3- phenoxypyridin-2-yl)thiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ 8.38 (d, 1H), 7.49(d, 1H), 7.43 (m, 2H), 7.22 (d, 1H), 7.19 (d, 1H), 7.12 (m, 2H), 6.77(s, 1H), 2.28 (s, 3H). Mass spectrum (apci) m/z = 413.1 (M + H − 2HCl).116

N-(3-(2- chlorophenylthio)-5- (pyridin-4- ylthio)pyridin-2-yl)-4-methylthiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ 8.58 (m, 2H),8.46 (s, 1H), 7.60 (m, 3H), 7.40 (m, 3H), 7.22 (bs, 1H), 6.53 (s, 1H),2.21 (s, 3H). Mass spectrum (apci) m/z = 443.2 (M + H − 2HCl). 117

4-(1-methylpiperidin- 4-yl)-N-(3-phenoxy-5- (phenylthio)pyridin-2-yl)thiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ 11.05 (bs, 1H),10.00 (bs, 1H), 8.20 (d, 1H), 7.40 (m, 2H), 7.32 (m, 2H), 7.25-7.15 (m,5H), 7.08 (m, 2H), 6.78 (s, 1H), 3.45 (m, 2H), 3.06 (m, 2H), 2.82 (m,1H), 2.75 (d, 3H), 2.15 (m, 2H), 1.85 (m, 2H). Mass spectrum (apci) m/z= 475.3 (M + H − 2HCl). 118

N-(3,5- bis(phenylthio)pyridin- 2-yl)-4-methylthiazol- 2-aminehydrochloride ¹H NMR (d₆-DMSO) δ 8.33 (s, 1H), 7.44-7.16 (m, 11H), 6.63(s, 1H), 2.24 (s, 3H). Mass spectrum (apci) m/z = 407.7 (M + H − HCl).119

4-methyl-N-(3- (phenylthio)-5- (pyridin-2- ylthio)pyridin-2-yl)thiazol-2-amine hydrochloride ¹H NMR (d₆-DMSO) δ 8.43 (s, 1H), 8.36(m, 1H), 7.68 (m, 1H), 7.61 (bs, 1H), 7.48-7.32 (m, 5H), 7.16 (m, 1H),7.07 (d, 1H), 6.66 (s, 1H), 2.25 (s, 3H). Mass spectrum (apci) m/z =408.7 (M + H − HCl). 120

3-methyl-N-(3- (phenylthio)-5- (pyridin-2- ylthio)pyridin-2-yl)-1,2,4-oxadiazol-5- amine dihydrochloride ¹H NMR (d₆-DMSO) δ 8.36 (ddd,1H), 8.30 (bs, 1H), 7.68 (m, 1H), 7.50-7.37 (m, 6H), 7.17 (m, 2H), 2.25(s, 3H). Mass spectrum (apci) m/z = 394.1 (M + H − 2HCl). 121

3-methyl-N-(3- phenoxy-5-(pyridin-2- ylthio)pyridin-2-yl)-1,2,4-thiadiazol-5- amine dihydrochloride ¹H NMR (d₆-DMSO) δ 12.30 (bs,1H), 8.37 (m, 2H), 7.67 (m, 1H), 7.43 (m, 3H), 7.15 (m, 5H), 2.43 (s,3H). Mass spectrum (apci) m/z = 394.2 (M + H − 2HCl). 122

N-(5-(4- methoxyphenylthio)-3- phenoxypyridin-2-yl)- 3-methyl-1,2,4-thiadiazol-5-amine hydrochloride ¹H NMR (d₆-DMSO) δ 12.10 (bs, 1H), 8.10(m, 1H), 7.38 (m, 4H), 7.18 (m, 1H), 7.14 (m, 1H), 7.05 (m, 2H), 6.94(m, 2H), 3.74 (s, 3H), 2.40 (s, 3H). Mass spectrum (apci) m/z = 423.2(M + H − HCl). 123

N-(3-(4- fluorophenoxy)-5- (pyridin-2- ylthio)pyridin-2-yl)-3-isobutyl-1,2,4- thiadiazol-5-amine ¹H NMR (CDCl₃) δ 9.13 (bs, 1H), 8.36(m, 1H), 8.33 (m, 1H), 7.50 (m, 1H), 7.28 (m, 1H), 7.09 (m, 4H), 7.02(m, 2H), 2.73 (d, 2H), 2.23 (m, 1H), 0.98 (d, 6H). Mass spectrum (apci)m/z = 454.2 (M + H).

Example 124(6-(4-Methylthiazol-2-ylamino)-5-phenoxypyridin-3-yl)methanol

To a mixture of mL6-(4-methylthiazol-2-ylamino)-5-phenoxynicotinaldehyde (Example 44, StepA; 150 mg, 0.48 mmol) and EtOH (5 mL) was added sodium borohydride (27.3mg, 0.72 mmol) and stirred at ambient temperature for 30 minutes. Pouredinto saturated aqueous NH₄Cl and extracted with CH₂Cl₂. The organiclayer was dried with sodium sulfate, filtered and concentrated. Theresidue was purified on silica gel (1:1 EtOAc:hexanes) to afford thetitle compound (132 mg, 87.4% yield) as a white solid. ¹H NMR (CDCl₃) δ8.66 (bs, 1H), 8.06 (d, 1H), 7.38 (m, 2H), 7.19 (m, 1H), 7.12 (d, 1H),7.03 (m, 2H), 6.42 (q, 1H), 4.58 (s, 2H), 2.33 (d, 3H), 1.77 (bs, 1H).

Example 125N-(5-(4-(dimethylamino)but-1-enyl)-3-phenoxypyridin-2-yl)-4-methylthiazol-2-aminedihydrochloride

A mixture of mL [3-(dimethylamino)propyl]-triphenylphosphonium bromide(413 mg, 0.964 mmol) and THF (5 mL) was cooled to 0° C. Butyllithium(0.385 mL, 0.964 mmol) was added and stirred at 0° C. for 20 minutes.6-(4-Methylthiazol-2-ylamino)-5-phenoxynicotinaldehyde (100 mg, 0.321mmol) was added and stirred at ambient temperature for minutes. Thereaction was poured into aqueous NH₄Cl and extracted with EtOAc. Theorganic layer was dried with sodium sulfate, filtered and concentrated.The residue was purified on silica gel (0 to 20% methanol in EtOAc) toafford both isomers of desired material as white solids after

HCl salt formation. Cis-isomer: ¹H NMR (CDCl₃) δ 12.82 (bs, 1H), 12.55(bs, 1H), 8.06 (s, 1H), 7.42 (m, 2H), 7.21 (m, 3H), 7.04 (m, 1H), 6.47(s, 1H), 6.39 (d, 1H), 5.67 (m, 1H), 3.05 (m, 2H), 2.84 (m, 2H), 2.74(d, 6H), 2.46 (s, 3H). Mass spectrum (apci) m/z=381.2 (M+H-2HCl).Trans-isomer: ¹H NMR (CDCl₃) δ 12.73 (bs, 1H), 12.50 (bs, 1H), 8.04 (d,1H), 7.41 (m, 2H), 7.21 (m, 4H), 6.43 (m, 2H), 6.02 (m, 1H), 3.09 (m,2H), 2.81 (m, 8H), 2.45 (s, 3H). Mass spectrum (apci) m/z=381.2(M+H-2HCl).

Example 1265-(4-(dimethylamino)butyl)-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-aminedihydrochloride

Prepared according to the method of Example 44, Step C from5-(4-(dimethylamino)but-1-enyl)-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine.¹H NMR (CDCl₃) δ 12.59 (bs, 1H), 12.25 (bs, 1H), 7.94 (s, 1H), 7.40 (m,2H), 7.21 (t, 1H), 7.15 (m, 2H), 7.03 (s, 1H), 6.42 (s, 1H), 2.96 (m,2H), 2.76 (d, 6H), 2.61 (t, 2H), 2.44 (s, 3H), 1.90 (m, 2H), 1.63 (m,2H). Mass spectrum (apci) m/z=383.2 (M+H-2HCl).

Example 1275-(2-chloropyridin-4-ylthio)-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-aminedihydrochloride

A mixture of methyl3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate(72 mg, 0.18 mmol), 2-chloro-4-nitropyridine (85.3 mg, 0.54 mmol) andDMSO (2.0 mL) and purged with nitrogen for 5 minutes. Potassium2-methylpropan-2-olate (60.4 mg, 0.54 mmol) was added and stirred for 30minutes. The reaction was poured into aqueous NH₄Cl and extracted withEtOAc (1×20 mL). The organic phase was washed with water, dried withsodium sulfate, filtered and concentrated. The residue was purified onsilica gel (25% EtOAc in hexanes) to afford the title compound (37.1 mg,41.4% yield) as a white solid after HCl salt formation. ¹H NMR (CDCl₃) δ12.89 (bs, 1H), 8.24 (m, 2H), 8.17 (d, 1H), 7.43 (t, 2H), 7.31 (d, 1H),7.28-7.18 (m, 3H), 6.88 (s, 1H), 6.84 (m, 1H), 6.53 (s, 1H), 3.93 (s,1H), 2.50 (s, 3H). Mass spectrum (apci) m/z=427.2 (M+H-2HCl).

The following compounds were prepared according to the method of Example127.

Example Structure Name Data 128

N-(5-(2-chloropyrimidin-4- ylthio)-3-phenoxypyridin-2-yl)-4-methylthiazol-2- amine dihydrochloride ¹H NMR (CDCl₃) δ 8.29 (d,1H), 8.24 (d, 1H), 7.42 (m, 3H), 7.26 (m, 3H), 6.94 (d, 1H), 6.52 (d,1H), 2.48 (d, 3H). Mass spectrum (apci) m/z = 428.2 (M + H − 2HCl). 129

5-(4,6-dimethylpyrimidin- 2-ylthio)-N-(4- methylthiazol-2-yl)-3-phenoxypyridin-2-amine dihydrochloride ¹H NMR (CDCl₃) δ 12.63 (bs, 1H),8.25 (m, 1H), 7.57 (m, 1H), 7.35 (t, 2H), 7.25 (m, 3H), 7.18 (m, 1H),6.73 (s, 1H), 6.46 (s, 1H), 2.47 (s, 3H), 2.34 (s, 6H). Mass spectrum(apci) m/z = 422.2 (M + H − 2HCl). 130

N-(5-(4,6- dimethoxypyrimidin-2- ylthio)-3-phenoxypyridin-2-yl)-4-methylthiazol-2- amine dihydrochloride ¹H NMR (d₆-DMSO) δ 8.30(d, 1H), 7.52 (d, 1H), 7.42 (m, 2H), 7.19 (t, 1H), 7.11 (d, 1H), 6.75(s, 1H), 5.97 (s, 1H), 3.70 (s, 6H), 2.28 (s, 3H). Mass spectrum (esi)m/z = 454.2 (M + H − 2HCl). 131

5-(4-methoxypyrimidin-2- ylthio)-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2- amine dihydrochloride ¹H NMR (d₆-DMSO) δ 8.30(m, 2H), 7.50 (m, 1H), 7.43 (m, 2H), 7.19 (m, 1H), 7.13 (d, 2H), 6.75(s, 1H), 6.67 (dd, 1H), 3.73 (s, 3H), 2.28 (s, 3H). Mass spectrum (esi)m/z = 424.2 (M + H − 2HCl). 132

N-(4-methoxythiazol-2-yl)- 3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin- 2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ8.58 (d, 1H), 8.42 (d, 1H), 8.34 (d, 1H), 7.68 (d, 1H), 7.47 (d, 1H),7.40 (m, 2H), 7.19-7.07 (m, 4H), 6.73 (s, 1H), 2.27 (s, 3H). Massspectrum (apci) m/z = 449.2 (M + H − 2HCl). 133

4-methyl-N-(5-(3- methylisoxazolo[5,4- b]pyridin-4-ylthio)-3-phenoxypyridin-2- yl)thiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ8.38 (m, 1H), 8.33 (dd, 1H), 7.42 (m, 3H), 7.17 (m, 3H), 6.74 (m, 2H),2.69 (s, 3H), 2.28 (s, 3H). Mass spectrum (apci) m/z = 448.2 (M + H −2HCl). 134

N-(5-(2- (methoxymethyl)pyrimidin- 4-ylthio)-3- phenoxypyridin-2-yl)-4-methylthiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ 8.48 (d, 1H),8.35 (dd, 1H), 7.49 (dd, 1H), 7.43 (m, 2H), 7.18 (m, 3H), 7.08 (d, 1H),6.80 (s, 1H), 4.44 (s, 2H), 3.30 (s, 3H), 2.30 (s, 3H). Mass spectrum(apci) m/z = 438.2 (M + H − 2HCl). 135

4-phenethyl-N-(3-phenoxy- 5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-yl)thiazol- 2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ8.54 (d, 1H), 8.40 (d, 1H), 8.25 (d, 1H), 7.63 (d, 1H), 7.45 (d, 1H),7.39 (m, 2H), 7.31-7.10 (m, 8H), 7.01 (d, 1H), 6.72 (s, 1H), 3.00-2.85(m, 4H). Mass spectrum (apci) m/z = 539.3 (M + H − 2HCl). 136

N-(5-(3- methylisoxazolo[5,4- b]pyridin-4-ylthio)-3-phenoxypyridin-2-yl)-4- phenethylthiazol-2-amine dihydrochloride ¹H NMR(d₆-DMSO) δ 8.38 (d, 1H), 8.33 (d, 1H), 7.42 (m, 3H), 7.31-7.15 (m, 8H),6.74 (m, 2H), 3.00-2.86 (m, 4H), 2.69 (s, 3H). Mass spectrum (apci) m/z= 538.3 (M + H − 2HCl). 137

N-(5-(5- methylpyrazolo[1,5- a]pyrimidin-7-ylthio)-3-phenoxypyridin-2-yl)-4- phenethylthiazol-2-amine dihydrochloride ¹H NMR(d₆-DMSO) δ 8.43 (d, 1H), 8.20 (d, 1H), 7.56 (d, 1H), 7.42 (m, 2h),7.31-7.14 (m, 8H), 6.75 (s, 1H), 6.57 (d, 1H), 6.31 (s, 1H), 3.00-2.87(m, 4H), 2.42 (s, 3H). Mass spectrum (apci) m/z = 537.3 (M + H − 2HCl).138

4-phenethyl-N-(3-phenoxy- 5-(thieno[3,2-d]pyrimidin- 4-ylthio)pyridin-2-yl)thiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ 8.90 (s, 1H), 8.43(m, 2H), 7.63 (d, 1H), 7.60 (d, 1H), 7.43 (m, 2H), 7.32-7.14 (m, 8H),6.80 (s, 1H), 3.01-2.90 (m, 4H). Mass spectrum (apci) m/z = 540.3 (M + H− 2HCl). 139

4-methyl-N-(5-(5- methylpyrazolo[1,5- a]pyrimidin-7-ylthio)-3-phenoxypyridin-2- yl)thiazol-2-amine ¹H NMR (d₆-DMSO) δ 11.28 (bs, 1H),8.42 (d, 1H), 8.20 (d, 1H), 7.53 (d, 1H), 7.40 (m, 2H), 7.22-7.10 (m,3H), 6.69 (s, 1H), 6.57 (d, 1H), 6.30 (s, 1H), 2.42 (s, 3H), 2.26 (s,3H). Mass spectrum (apci) m/z = 447.2 (M + H). 140

4-methyl-N-(3-phenoxy-5- (thieno[3,2-d]pyrimidin-4-ylthio)pyridin-2-yl)thiazol- 2-amine ¹H NMR (d₆-DMSO) δ 11.18 (bs, 1H),8.89 (s, 1H), 8.42 (d, 1H), 8.39 (d, 1H), 7.62 (d, 1H), 7.55 (d, 1H),7.40 (m, 2H), 7.18-7.10 (m, 3H), 6.67 (s, 1H), 2.26 (s, 3H). Massspectrum (apci) m/z = 450.2 (M + H). 141

4-(1-methylpiperidin-4-yl)- N-(3-phenoxy-5- (thieno[3,2-b]pyridin-7-ylthio)pyridin-2-yl)thiazol- 2-amine trihydrochloride ¹H NMR (d₆-DMSO) δ10.63 (bs, 1H), 8.62 (m, 1H), 8.43 (m, 2H), 7.74 (d, 1H), 7.51 (t, 1H),7.41 (m, 2H), 7.16 (m, 4H), 6.85 (s, 1H), 3.46 (m, 2H), 3.05 (m, 2H),2.85 (m, 1H), 2.73 (d, 3H), 2.15 (m, 2H), 1.94 (m, 2H). Mass spectrum(apci) m/z = 532.3 (M + H − 3HCl). 142

N-(5-(3- methylisoxazolo[5,4- b]pyridin-4-ylthio)-3-phenoxypyridin-2-yl)-4-(1- methylpiperidin-4- yl)thiazol-2-aminetrihydrochloride ¹H NMR (d₆-DMSO) δ 11.53 (bs, 1H), 10.34 (bs, 1H), 8.38(d, 1H), 8.33 (d, 1H), 7.42 (m, 3H), 7.18 (m, 3H), 6.84 (s, 1H), 6.73(d, 1H), 3.47 (m, 2H), 3.05 (m, 2H), 2.85 (m, 1H), 2.74 (d, 3H), 2.69(s, 3H), 2.16 (m, 2H), 1.90 (m, 2H). Mass spectrum (apci) m/z = 531.3(M + H − 3HCl). 143

N-(5-(2-iodothieno[3,2- b]pyridin-7-ylthio)-3- phenoxypyridin-2-yl)-4-methylthiazol-2-amine ¹H NMR (CDCl₃) δ 8.86 (bs, 1H), 8.37 (m, 1H), 8.29(m, 1H), 7.75 (s, 1H), 7.39 (m, 3H), 7.20 (m, 1H), 7.16 (m, 1H), 7.05(m, 2H), 6.70 (d, 1H), 6.50 (m, 1H), 2.36 (s, 3H). Mass spectrum (apci)m/z = 575.1 (M + H). 144

4-methyl-N-(5-(2- methylthieno[3,2- b]pyridin-7-ylthio)-3-phenoxypyridin-2- yl)thiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ8.87 (dd, 1H), 8.45 (dd, 1H), 7.54 (m, 2H), 7.41 (m, 2H), 7.17 (m, 4H),6.78 (s, 1H), 2.74 (s, 3H), 2.29 (s, 3H). Mass spectrum (apci) m/z =463.2 (M + H − 2HCl). 145

N-(5-(2-methylthieno[3,2- b]pyridin-7-ylthio)-3- phenoxypyridin-2-yl)-4-phenethylthiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ 8.56 (d,1H), 8.43 (d, 1H), 7.52 (m, 2H), 7.41 (m, 2H), 7.31-7.11 (m, 9H), 6.76(s, 1H), 3.00-2.87 (m, 4H), 2.73 (s, 3H). Mass spectrum (apci) m/z =553.3 (M + H − 2HCl). 146

N-(5-(2,5- dimethylpyrazolo[1,5- a]pyrimidin-7-ylthio)-3-phenoxypyridin-2-yl)-4- phenethylthiazol-2-amine dihydrochloride ¹H NMR(d₆-DMSO) δ 8.42 (dd, 1H), 7.54 (dd, 1H), 7.42 (m, 2H), 7.31-7.15 (m,8H), 6.76 (s, 1H), 6.37 (s, 1H), 6.21 (s, 1H), 3.00-2.87 (m, 4H), 2.42(s, 3H), 2.38 (s, 3H). Mass spectrum (apci) m/z = 551.3 (M + H − 2HCl).147

N-(3-(4-fluorophenoxy)-5- (thieno[3,2-b]pyridin-7-ylthio)pyridin-2-yl)-4- phenethylthiazol-2-amine dihydrochloride ¹H NMR(d₆-DMSO) δ 8.62 (d, 1H), 8.42 (m, 2H), 7.73 (d, 1H), 7.51 (d, 1H),7.31-7.13 (m, 10H), 6.77 (s, 1H), 3.01-2.88 (m, 4H). Mass spectrum(apci) m/z = 557.3 (M + H − 2HCl). 148

N-(3-(4-fluorophenoxy)-5- (3-methylisoxazolo[5,4-b]pyridin-4-ylthio)pyridin- 2-yl)-4-phenethylthiazol-2- aminedihydrochloride ¹H NMR (d₆-DMSO) δ 8.38 (d, 1H), 8.32 (d, 1H), 7.45 (d,1H), 7.31-7.16 (m, 9H), 6.80 (s, 1H), 6.74 (d, 1H), 3.02-2.90 (m, 4H),2.69 (s, 3H). Mass spectrum (apci) m/z = 556.3 (M + H − 2HCl). 149

N-(3-(4-fluorophenoxy)-5- (5-methylpyrazolo[1,5- a]pyrimidin-7-ylthio)pyridin-2-yl)-4- phenethylthiazol-2-amine dihydrochloride ¹H NMR(d₆-DMSO) δ 8.42 (m, 1H), 8.20 (d, 1H), 7.54 (d, 1H), 7.31-7.16 (m, 9H),6.75 (s, 1H), 6.57 (d, 1H), 6.30 (s, 1H), 3.01-2.88 (m, 4H), 2.42 (s,3H). Mass spectrum (apci) m/z = 555.2 (M + H − 2HCl). 150

N-(5-(2,5- dimethylpyrazolo[1,5- a]pyrimidin-7-ylthio)-3-(4-fluorophenoxy)pyridin-2- yl)-4-phenethylthiazol-2- amine dihydrochloride¹H NMR (d₆-DMSO) δ 8.40 (m, 1H), 7.52 (m, 1H), 7.31-7.16 (m, 9H), 6.75(s, 1H), 6.37 (s, 1H), 6.20 (m, 1H), 3.01-2.88 (m, 4H), 2.42 (s, 3H),2.38 (s, 3H). Mass spectrum (apci) m/z = 569.2 (M + H − 2HCl). 151

N-(3-(4-fluorophenoxy)-5- (2-methylthieno[3,2-b]pyridin-7-ylthio)pyridin- 2-yl)-4-phenethylthiazol-2- aminedihydrochloride ¹H NMR (d₆-DMSO) δ 8.55 (m, 1H), 8.41 (m, 1H), 7.50 (m,2H), 7.31-7.16 (m, 9H), 7.10 (d, 1H), 6.75 (s, 1H), 3.01-2.88 (m, 4H),2.73 (s, 3H). Mass spectrum (apci) m/z = 571.3 (M + H − 2HCl). 152

4-(6-(4-methylthiazol-2- ylamino)-5- phenoxypyridin-3-ylthio)benzonitrile hydrochloride ¹H NMR (d₆-DMSO) δ 8.30 (m, 1H), 7.71(d, 2h), 7.41 (t, 2H), 7.33 (m, 1H), 7.26 (d, 2H), 7.18 (t, 1H), 7.12(d, 2H), 6.72 (s, 1H), 2.27 (s, 3H). Mass spectrum (apci) m/z = 417.0(M + H − 2HCl). 153

N-(3-(2-chlorophenylthio)- 5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-yl)-4- methylthiazol-2-amine dihydrochloride ¹H NMR(d₆-DMSO) δ 8.66 (dd, 1H), 8.54 (d, 1H), 8.49 (d, 1H), 7.78 (dd, 1h),7.58 (m, 1H), 7.43-7.31 (m, 4H), 7.12 (d, 1H), 6.56 (s, 1H), 2.22 (s,3H). Mass spectrum (esi) m/z = 498.8 (M + H − 2HCl). 154

4-(5-phenoxy-6-(4- (piperidin-4-yl)thiazol-2- ylamino)pyridin-3-ylthio)benzonitrile dihydrochloride ¹H NMR (d₆-DMSO) δ 11.30 (bs, 1H),9.01 (m, 1H), 8.85 (m, 1H), 8.30 (m, 1H), 7.72 (m, 2H), 7.45-7.10 (m.,8H), 6.82 (s, 1H), 3.57 (m, 1H), 3.31 (m, 2H), 2.96 (m, 3H), 2.12 (m,2H), 1.82 (m, 2H). Mass spectrum (apci) m/z = 485.6 (M + H − 2HCl). 155

N-(5-(furo[3,2-c]pyridin-4- ylthio)-3-phenoxypyridin-2-yl)-4-methylthiazol-2- amine dihydrochloride ¹H NMR (d₆-DMSO) δ 8.28(m, 1H), 8.19 (m, 1H), 8.09 (m, 1H), 7.48 (m, 1H), 7.41 (m, 1H), 7.37(m, 2H), 7.11 (m, 3H), 6.89 (m, 1H), 6.74 (s, 1H), 2.24 (s, 3H). Massspectrum (apci) m/z = 433.2 (M + H − 2HCl). 156

N-(5-(2-iodothieno[3,2- b]pyridin-7-ylthio)-3- phenoxypyridin-2-yl)-4-(piperidin-4-yl)thiazol-2- amine trihydrochloride ¹H NMR (d₆-DMSO) δ11.25 (bs, 1H), 8.80 (m, 1H), 8.58 (m, 1H), 8.44 (m, 1H), 8.38 (m, 1H),7.40 (m, 3H), 7.12 (m, 4H), 6.95 (m, 1H), 6.81 (s, 1H0, 3.32 (m, 2H),2.96 (m, 3H), 2.12 (m, 2H), 1.78 (m, 2H). Mass spectrum (apci) m/z =644.3 (M + H − 3HCl). 157

4-methyl-N-(3- (phenylthio)-5-(thieno[3,2- b]pyridin-7-ylthio)pyridin-2-yl)thiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ 8.56 (d, 1H),8.43 (s, 1H), 8.32 (d, 1H), 7.67 (d, 1H), 7.47 (m, 2H), 7.39 (m, 3H),7.26 (bs, 1H), 6.96 (d, 1H), 6.52 (s, 1H), 2.22 (s, 3H). Mass spectrum(apci) m/z = 464.7 (M + H − 2HCl). 158

4-methyl-N-(5-(3- methylisoxazolo[5,4- b]pyridin-4-ylthio)-3-(phenylthio)pyridin-2- yl)thiazol-2-amine dihydrochloride ¹H NMR(d₆-DMSO) δ 8.40 (bs, 1H), 8.32 (d, 1H), 7.51 (m, 2H), 7.40 (m, 3H),7.25 (bs, 1H), 6.61 (d, 1H), 6.52 (s, 1H), 2.67 (s, 3H), 2.22 (s, 3H).Mass spectrum (apci) m/z = 463.6 (M + H − 2HCl). 159

4-(6-(4-methylthiazol-2- ylamino)-5- (phenylthio)pyridin-3-ylthio)benzonitrile hydrochloride ¹H NMR (d₆-DMSO) δ 8.36 (s, 1H), 7.71(m, 2H), 7.48-7.35 (m, 5H), 7.19 (m, 2H), 6.55 (s, 1H), 2.22 (s, 3H).Mass spectrum (apci) m/z = 431.9 (M + H − HCl). 160

4-methyl-N-(3- (phenylthio)-5-(5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-4- ylthio)pyridin-2-yl)thiazol- 2-amine trihydrochloride ¹HNMR (d₆-DMSO) δ 9.67 (bs, 2H), 8.71 (s, 1H), 8.29 (s, 1H), 7.50-7.35 (m,6H), 6.53 (s, 1H), 4.18 (m, 2H), 3.47 (m, 2H), 3.04 (t, 2H), 2.21 (s,3H). Mass spectrum (apci) m/z = 464.7 (M + H − 3HCl). 161

tert-butyl 4-(5-(3-(4- fluorophenoxy)-5- (thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)- 1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate ¹H NMR (CDCl₃) δ 9.16 (s, 1H), 8.49 (d, 1H),8.37 (d, 1H), 7.74 (d, 1H), 7.56 (d, 1H), 7.17 (d, 1H), 7.08 (m, 4H),6.76 (d, 1H), 4.16 (m, 2H), 3.00 (m, 1H), 2.91 (m, 2H), 2.05 (m, 2H),1.82 (m, 2H), 1.47 (s, 9H). Mass spectrum (apci) m/z = 537.2 (M + H −Boc).

Example 162N-(4-cyclopropylthiazol-2-yl)-3-phenoxy-5-(pyridin-4-ylthio)pyridin-2-aminedihydrochloride

Step A: Preparation of 4-(2-(pyridin-4-yl)disulfanyl)pyridine: A mixtureof 5-bromo-3-phenoxypyridin-2-amine (2.1 g, 7.9 mmol) THF (80 mL) waspurged with nitrogen and cooled to −78° C. Methyllithium (5.9 mL, 9.5mmol) was added and stirred for 5 minutes. Butyllithium (3.8 mL, 9.5mmol) was added and stirred for 10 minutes at −78° C.4-(2-(Pyridin-4-yl)disulfanyl)pyridine (4.4 g, 20 mmol) was added andwarmed to ambient temperature. The reaction was poured into saturatedaqueous NH₄Cl and extracted with EtOAc. The organic layer was dried,filtered and concentrated. The residue was dissolved in methanol andNaBH₄ (excess) added. The reaction was poured into saturated aqueousNH₄Cl and extracted with EtOAc (2×75 mL). The organic layer was driedwith sodium sulfate, filtered and concentrated. The residue was purifiedon silica gel (50% EtOAc in hexanes to 5% methanol in EtOAc) to affordthe title compound (4.4 g, 20 mmol).

Steps B-D: Preparation ofN-(4-cyclopropylthiazol-2-yl)-3-phenoxy-5-(pyridin-4-ylthio)pyridin-2-aminedihydrochloride: Prepared according to the method of Example 7, StepsC-E. ¹H NMR (d₆-DMSO) δ 8.52 (m, 2H), 8.34 (d, 1H), 7.52 (m, 2H), 7.42(m, 3H), 7.17 (m, 3H), 6.72 (s, 1H), 1.97 (m, 1H), 0.84 (m, 2H), 0.78(m, 2H). Mass spectrum (apci) m/z=419.3 (M+H-2HCl).

The following compounds were prepared according to the method of Example7, Step E.

Example Structure Name Data 163

4-isobutyl-N-(3- phenoxy-5-(pyridin-4- ylthio)pyridin-2-yl)thiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ 8.57 (m, 2H), 8.38(dd, 1H), 7.63 (m, 2H), 7.47 (dd, 1H), 7.42 (m, 2H), 7.17 (m, 3H), 6.74(s, 1H), 2.47 (d, 2H), 2.00 (m, 1H), 0.89 (d, 6H). Mass spectrum (apci)m/z = 435.3 (M + H − 2HCl). 164

4-cyclohexyl-N-(3- phenoxy-5-(pyridin-4- ylthio)pyridin-2-yl)thiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ 8.57 (m, 2H), 8.38(dd, 1H), 7.63 (m, 2H), 7.48 (d, 1H), 7.42 (m, 2H), 7.17 (m, 3H), 6.72(s, 1H), 2.59 (m, 1H), 1.97 (m, 2H), 1.80-1.65 (m, 3H), 1.46-1.14 (m,5H). Mass spectrum (apci) m/z = 461.3 (M + H − 2HCl). 165

N-(3-phenoxy-5- (pyridin-4- ylthio)pyridin-2-yl)-4-(trifluoromethyl)thiazol- 2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ12.08 (s, 1H), 8.57 (m, 2H), 8.44 (dd, 1H), 7.92 (s, 1H), 7.62 (m, 2H),7.56 (dd, 1H), 7.43 (m, 2H), 7.19 (m, 3H). Mass spectrum (apci) m/z =447.3 (M + H − 2HCl). 166

methyl 3-(2-(3- phenoxy-5-(pyridin-4- ylthio)pyridin-2-ylamino)thiazol-4- yl)propanoate dihydrochloride ¹H NMR (d₆-DMSO) δ 8.56(m, 2H), 8.37 (d, 1H), 7.62 (m, 2H), 7.46 (d, 1H), 7.42 (m, 2H), 7.17(m, 3H), 6.77 (s, 1H), 3.59 (s, 3H), 2.87 (t, 2H), 2.70 (t, 2H). Massspectrum (apci) m/z = 465.2 (M + H − 2HCl). 167

N-(3-phenoxy-5- (pyridin-4- ylthio)pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2- amine trihydrochloride ¹H NMR (d₆-DMSO) δ 11.70(bs, 1H), 8.70 (m, 1H), 8.59 (m, 2H), 8.44 (d, 1H), 8.25 (m, 3H), 7.68(m, 2H), 7.62 (m, 1H), 7.53 (d, 1H), 7.44 (m, 2H), 7.22 (m, 3H). Massspectrum (apci) m/z = 456.3 (M + H − 3HCl). 168

N-(3-phenoxy-5- (pyridin-4- ylthio)pyridin-2-yl)-4-phenylthiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ 11.55 (bs, 1H),8.57 (d, 2H), 8.41 (dd, 1H), 7.95 (d, 2H), 7.65 (d, 2H), 7.62 (s, 1H),7.48 (d, 1H), 7.43 (m, 4H), 7.32 (t, 1H), 7.21 (m, 3H). Mass spectrum(apci) m/z = 455.3 (M + H − 2HCl). 169

N-(3-phenoxy-5- (pyridin-4- ylthio)pyridin-2-yl)-4-(thiophen-3-yl)thiazol- 2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ 11.55(bs, 1H), 8.58 (d, 2H), 8.40 (d, 1H), 7.81 (m, 1H), 7.67 (d, 2H), 7.59(m, 2H), 7.50 (d, 1H), 7.43 (m, 3H), 7.20 (m, 3H). Mass spectrum (apci)m/z = 461.2 (M + H − 2HCl). 170

4-phenethyl-N-(3- phenoxy-5-(pyridin-4- ylthio)pyridin-2-yl)thiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ 8.58 (m, 2H), 8.38(dd, 1H), 7.65 (m, 2H), 7.48 (dd, 1H), 7.42 (m, 2H), 7.31-7.14 (m, 8H),6.74 (s, 1H), 2.96 (m, 2H), 2.90 (m, 2H). Mass spectrum (apci) m/z =483.3 (M + H − 2HCl). 171

4-ethyl-N-(3-phenoxy- 5-(pyridin-4- ylthio)pyridin-2- yl)thiazol-2-aminedihydrochloride ¹H NMR (d₆-DMSO) δ 8.58 (m, 2H), 8.38 (d, 1H), 7.65 (m,2H), 7.48 (d, 1H), 7.42 (m, 2H), 7.17 (m, 3H), 6.74 (s, 1H), 2.63 (q,2H), 1.21 (t, 3H). Mass spectrum (apci) m/z = 407.3 (M + H − 2HCl). 172

N-(3-phenoxy-5- (pyridin-4- ylthio)pyridin-2- yl)thiazol-2-aminedihydrochloride ¹H NMR (d₆-DMSO) δ 8.54 (m, 2H), 8.38 (m, 1H), 7.55 (m,2H), 7.49 (dd, 1H), 7.43 (m, 3H), 7.18 (m, 4H). Mass spectrum (apci) m/z= 379.2 (M + H − 2HCl). 173

4-isopropyl-N-(3- phenoxy-5-(pyridin-4- ylthio)pyridin-2-yl)thiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ 8.58 (m, 2H), 8.38(m, 1H), 7.63 (m, 2H), 7.47 (m, 1H), 7.42 (m, 2H), 7.18 (m, 3H), 6.72(s, 1H), 2.92 (m, 1H), 1.24 (d, 6H). Mass spectrum (apci) m/z = 421.3(M + H − 2HCl).

Example 174N-(5-bromo-3-phenoxypyridin-2-yl)-4-(piperidin-4-yl)thiazol-2-aminedihydrochloride

Step A: Following the procedure in Example 7, step E using1-(5-bromo-3-phenoxypyridin-2-yl)thiourea and tert-butyl4-(2-bromoacetyl)piperidine-1-carboxylate provided tert-butyl4-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate.

Step B: tert-Butyl4-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylatewas dissolved in 1:1CH₂Cl₂:methanol and 4N HCl in dioxane was added andstirred at room temperature for 1 hour. The solvents were removed toafford the title compound. ¹H NMR (d₆-DMSO) δ 10.98 (bs, 1H), 8.90 (bs,1H), 8.70 (bs, 1H), 8.23 (d, 1H), 7.45 (m, 2H), 7.40 (d, 1H), 7.22 (m,1H), 7.12 (m, 2H), 6.76 (s, 1H), 3.31 (m, 2H), 2.98 (m, 2H), 2.89 (m,1H), 2.10 (m, 2H), 1.79 (m, 2H). Mass spectrum (apci) m/z=431.2, 433.2(M+H-2HCl).

Example 175N-(5-bromo-3-phenoxypyridin-2-yl)-4-(1-methylpiperidin-4-yl)thiazol-2-aminedihydrochloride

To a mixture of5-bromo-3-phenoxy-N-(4-(piperidin-4-yl)thiazol-2-yl)pyridin-2-aminedihydrochloride (80 mg, 0.16 mmol), paraformaldehyde (7.15 mg, 0.24mmol), and ClCH₂CH₂Cl (2 mL) was added NaBH(OAc)₃ (134 mg, 0.64 mmol)and the reaction was stirred at ambient temperature for 2 days. Pouredinto saturated aqueous NaHCO₃ and extracted with EtOAc. The organiclayer was dried with sodium sulfate, filtered and concentrated. Theresidue was purified on silica gel (10% methanol in EtOAc with 0.2% NH₃)to afford the title compound (51.2 mg, 62.3% yield) as a white solidafter HCl salt formation. ¹H NMR (d₆-DMSO) δ 11.00 (bs, 1H), 10.22 (bs,1H), 8.23 (s, 1H), 7.48-7.38 (m, 3H), 7.22 (t, 1H), 7.12 (m, 2H), 6.77(s, 1H), 3.46 (m, 2H), 3.05 (m, 2H), 2.82 (m, 1H), 2.74 (d, 3H), 2.14(m, 2H), 1.88 (m, 2H). Mass spectrum (apci) m/z=445.3 (M+H-2HCl).

Example 1762-(4-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanoldihydrochloride

Prepared according to the method of Example 175. ¹H NMR (d₆-DMSO) δ11.00 (bs, 1H), 9.94 (bs, 1H), 8.23 (d, 1H), 7.48-7.38 (m, 3H), 7.23 (m,1H), 7.12 (m, 2H), 6.76 (s, 1H), 3.79 (m, 2H), 3.74 (m, 1H), 3.58 (m,2H), 3.23-3.02 (m, 4H), 2.85 (m, 1H), 2.16 (m, 2H), 1.93 (m, 2H). Massspectrum (apci) m/z=475.3 (M+H-2HCl).

Example 1771-(4-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-ylpiperidin-1-yl)ethanonehydrochloride

To mL5-bromo-3-phenoxy-N-(4-(piperidin-4-yl)thiazol-2-yl)pyridin-2-aminedihydrochloride (80 mg, 0.159 mmol), triethylamine (0.088 mL, 0.64 mmol)and THF (2 mL) was added acetic anhydride (0.015 mL, 0.16 mmol) andstirred at ambient temperature for 30 minutes. Poured into saturatedaqueous NaHCO₃ and extract with EtOAc (2×20 mL). The organic layer wasdried with sodium sulfate, filtered and concentrated. The residue waspurified on silica gel (5% methanol in EtOAc) to afford the titlecompound (47.6 mg, 58.8% yield) as a white solid after HCl saltformation. ¹H NMR (d₆-DMSO) δ 11.00 (bs, 1H), 8.23 (d, 1H), 7.44 (m,2H), 7.40 (d, 1H), 7.21 (t, 1H), 7.11 (d, 2H), 6.70 (s, 1H), 4.41 (d,1H), 3.12 (m, 1H), 2.83 (tt, 1H), 2.62 (td, 1H), 2.50 (m, 1H), 2.00 (s,3H), 1.93 (m, 2H), 1.55 (qd, 1H), 1.42 (qd, 1H). Mass spectrum (apci)m/z=475.2 (M+H—HCl).

Example 178 N-(5-Bromo-3-phenoxypyridin-2-yl)-4-phenethylthiazol-2-amine

Prepared according to the method of Example 7 Step E from1-(5-bromo-3-phenoxypyridin-2-yl)thiourea and1-bromo-4-phenylbutan-2-one. ¹H NMR (d₆-DMSO) δ 8.26 (m, 1H), 7.45 (m,3H), 7.31-7.11 (m, 81H), 6.74 (s, 1H), 2.92 (m, 4H). Mass spectrum(apci) m/z=452.3 (M+H).

Example 179N-(5-Bromo-3-(4-fluorophenoxy)pyridin-2-yl)-4-phenethylthiazol-2-amine

Step A: 5-bromo-3-(4-fluorophenoxy)picolinonitrile: To a solution of4-fluorophenol (0.49 g, 4.4 mmol) in DMF (10 mL) cooled to 0° C. wasadded 60% sodium hydride (0.19 g, 4.8 mmol) was added and the reactionwas warmed to ambient temperature. 5-Bromo-3-nitropicolinonitrile (1.0g, 4.4 mmol, solution in 5 mL DMF) and stirred for 3 hours. Poured intowater, filtered, washed with water, and dried to yield the titlecompound (1.0 g, 78%).

Step B: 5-bromo-3-(4-fluorophenoxy)picolinamide To5-bromo-3-(4-fluorophenoxy)picolinonitrile (48.5 g, 165 mmol) was addedconcentrated sulfuric acid (200 mL) and stirred overnight at ambienttemperature, then added portionwise to water (1000 mL) cooled in an icebath at a rate such that the solution temperature did not exceed above35° C. The aqueous layer was extracted with ethyl acetate. The combinedorganics were washed with water, brine, dried, and concentrated to 200mL, filtered and dried to yield the title compound (49 g, 95%).

Step C: 5-bromo-3-(4-fluorophenoxy)pyridin-2-amine: To a solution of 2Msodium hydroxide (300 mL) at 0° C. was added bromine (6.94 mL, 135mmol). The reaction was stirred at 0° C. for 15 minutes, followed byaddition of 5-bromo-3-(4-fluorophenoxy)picolinamide (35 g, 113 mmol) indioxanes (600 mL). Stirred at room temperature for 1 hour, then heatedat 80° C. for 2 hours. The reaction was acidified with 1N HCl (800 mL)until no off gas was produced. The aqueous layer was basified using 1NNaOH. The aqueous layer was extracted with ethyl acetate. The organiclayer was washed with water, brine, dried and concentrated. The residuewas purified by chromatography using 15% ethyl acetate/CH₂Cl₂ as eluentto yield the title compound (27.3 g, 86%).

Step D: Following the procedure in Example 7, Step C,5-bromo-3-(4-fluorophenoxy)pyridin-2-amine (800 mg, 2.83 mmol) andbenzoyl isothiocyanate (0.457 mL, 3.39 mmol) afforded1-benzoyl-3-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (1150 mg,91.2% yield).

Step E: Following the procedure in Example 7, Step D,1-benzoyl-3-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (1150 mg,2.58 mmol) and 3M sodium hydroxide (1.7 mL, 5.1 mmol) provided1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (743 mg, 84.3%yield) as a white solid.

Step F: Following the procedure in Example 7 Step E,1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (740 mg, 2.163mmol), 1-bromo-4-phenylbutan-2-one (687.6 mg, 3.028 mmol) andtriethylamine (0.5014 mL, 3.676 mmol) afforded5-bromo-3-(4-fluorophenoxy)-N-(4-phenethylthiazol-2-yl)pyridin-2-amine(1040 mg, 102.2% yield) as a white solid after drying. ¹H NMR (CDCl₃) δ8.71 (bs, 1H), 8.13 (d, 1H), 7.28 (m, 2H), 7.20 (m, 3H), 7.13 (m, 2H),7.06 (m, 3H), 6.43 (s, 1H), 3.05-2.92 (m, 4H), Mass spectrum (apci)m/z=470.2, 472.2 (M+H).

Example 180N-(5-Bromo-3-(phenylthio)pyridin-2-yl)-4-methylthiazol-2-amine

Step A: Preparation of 2-nitro-3-(phenylthio)pyridine:3-chloro-2-nitropyridine (30.6 g, 193 mmol) was dissolved in DMSO (200mL). Benzenethiol (20.7 mL, 203 mmol) was added followed by cesiumcarbonate (69.3 g, 212 mmol) and stirred at ambient temperature for 1.5hours. The solution was diluted with water (750 mL) and the solidsfiltered. The crude material was recrystallized from EtOAc (400 mL) andwith adding hexanes (1 L) to give an A-crop of 23.5 g. The filtrate wasconcentrated and recrystallized from EtOAc/hexanes to give 7.87 g. Thesolids were dried on high vacuum to provide the title compound (31.38 g,69.8% yield).

Step B: Preparation of 5-bromo-3-(phenylthio)pyridin-2-amine: mL2-Nitro-3-(phenylthio)pyridine (16.3 g, 70.2 mmol) and AcOH (250 mL)were cooled in a water bath. Zinc (22.9 g, 351 mmol) was slowly addedand stirred for 5 minutes. Filtered through celite and the cake washedwith CH₂Cl₂. The CH₂Cl₂ was removed and to the solution was addedbromine (3.6 mL, 70.2 mmol). After 10 minutes, the HOAc was removed andpartitioned between EtOAc and saturated aqueous sodium bicarbonate. Theorganic layer was dried with sodium sulfate, filtered and concentrated.The residue was purified on silica gel (1.5 L SiO₂ and 30% EtOAc inhexanes) to afford the title compound (18.2 g, 92.21% yield).

Step C: Preparation of1-benzoyl-3-(5-bromo-3-(phenylthio)pyridin-2-yl)thiourea: mL5-Bromo-3-(phenylthio)pyridin-2-amine (17 g, 60.5 mmol), benzoylisothiocyanate (9.79 mL, 72.6 mmol), and THF (300 mL) was stirred at 40°C. overnight. Concentrated to half of the original volume and 9:1hexanes:EtOAc (500 mL) was added. Filtered to afford the title compound(25.7 g, 95.7% yield).

Step D: Preparation of 1-(5-bromo-3-(phenylthio)pyridin-2-yl)thiourea:To 1-Benzoyl-3-(5-bromo-3-(phenylthio)pyridin-2-yl)thiourea (25.7 g,57.8 mmol) and MeOH (250 mL) was added sodium hydroxide (38.6 mL, 116mmol) and stirred at ambient temperature for 8 hours. Diluted with water(250 mL) and filtered and washed with water. The precipitate was driedin vacuum oven to afford the title compound (19.0 g, 96.5% yield).

Step E: Preparation of5-bromo-N-(4-methylthiazol-2-yl)-3-(phenylthio)pyridin-2-amine: mL1-(5-Bromo-3-(phenylthio)pyridin-2-yl)thiourea (5.0 g, 14.69 mmol),triethylamine (6.0 mL, 44 mmol), 1-chloropropan-2-one (2.3 mL, 29.4mmol), and EtOH (100 mL) were heated to 70° C. for 6 hours. The ethanolwas reduced to ˜½ volume and water (150 mL) added and the precipitatewas filtered to afford the title compound (5.6 g, 100% yield) as a tansolid after drying. ¹H NMR (CDCl₃) δ 9.01 (s, 1H), 8.42 (m, 1H), 7.92(m, 1H), 7.32-7.15 (m, 5H), 6.44 (m, 1H0, 2.32 (m, 3H). Mass spectrum(apci) m/z=379.8 (M+H).

Example 181N-(5-bromo-3-(phenylthio)pyridin-2-yl)thiazolo[5,4-b]pyridin-2-aminehydrochloride

mL 5-Bromo-3-(phenylthio)pyridin-2-amine (1.0 g, 3.6 mmol),2-chloro-3-isothiocyanatopyridine (0.61 g, 3.6 mmol), DMF (2 mL) wereheated to 90° C. for 8 hours. Cooled to ambient temperature and thesolids were diluted with mL CH₂Cl₂ (2 mL) and filtered and washed withsmall amount of CH₂Cl₂ to afford the title compound (0.98 g, 61% yield).¹H NMR (d₆-DMSO) δ 8.50 (d, 1H), 8.39 (dd, 1H), 7.98 (s, 1H), 7.92 (dd,1 h), 7.38-7.25 (m, 6H). Mass spectrum (apci) m/z=414.8 (M+H).

Example 182N-(5-Bromo-3-(phenylthio)pyridin-2-yl)-3-methyl-1,2,4-oxadiazol-5-amine

Step A: Preparation of methylN′-5-bromo-3-(phenylthio)pyridin-2-yl-N-(1-(dimethylamino)ethylidene)carbamimidothioate:1-(5-Bromo-3-(phenylthio)pyridin-2-yl)thiourea (100 mg, 0.29 mmol) and1,1-dimethoxy-N,N-dimethylethanamine (0.096 mL, 0.59 mmol) were heatedto 70° C. for 1 hour. The reaction was cooled to ambient temperature toafford 120 mg of the title compound as a crude mixture.

Step B: Preparation of5-bromo-N-(3-methyl-1,2,4-oxadiazol-5-yl)-3-(phenylthio)pyridin-2-amine:ToN′-5-Bromo-3-(phenylthio)pyridin-2-yl-N-(1-(dimethylamino)ethylidene)carbamimidothioate(120 mg, 0.283 mmol), sodium acetate (69.8 mg, 0.850 mmol), and THF (2mL) was added hydroxylamine hydrochloride (59.1 mg, 0.850 mmol) followedby 0.1 mL water. Stirred at 50° C. for 3 hours and poured into saturatedaqueous NaHCO₃ and extracted with EtOAc. The organic layer was driedwith sodium sulfate, filtered and concentrated. The residue was purifiedon silica gel (1:1 EtOAc in hexanes) to afford the title compound (89mg, 86.5% yield). ¹H NMR (CDCl₃) δ 8.54 (m, 1H), 8.49 (bs, 1H), 7.96 (m,1H), 7.64-7.49 (m, 1H), 7.31 (m, 3H), 7.21 (m, 2H), 2.35 (s, 3H). Massspectrum (apci) m/z=362.4, 364.2 (M+H).

Example 183N-(5-bromo-3-phenoxypyridin-2-yl)-3-(tetrahydrofuran-2-yl)-1,2,4-thiadiazol-5-amine

Step A: Preparation of tetrahydrofuran-2-carbaldehyde oxime:Tetrahydrofuran-2-carbaldehyde (100 g, 500 mmol, 50 wt % in water) wasdissolved in methanol:water (1:1, 1500 mL) and cooled in an ice bath.Sodium carbonate (26.5 g, 250 mmol) and hydroxylamine hydrochloride(41.6 g, 600 mmol) were added and the reaction was stirred overnight atambient temperature. The reaction was concentrated to half volume andextracted with EtOAc (2×800 mL). The organic layer was dried overmagnesium sulfate, filtered and concentrated to afford the titlecompound (44.3 g, 80%).

Step B: Preparation of tetrahydrofuran-2-carbonyl chloride oxime: A 250mL round-bottomed flask was charged with tetrahydrofuran-2-carbaldehydeoxime (2.0 g, 17 mmol) and DMF (100 mL). 1-chloropyrrolidine-2,5-dione(2.3 g, 17 mmol) was added and stirred at ambient temperature overnight.The reaction was poured into 1:1 brine:water (800 mL) and extracted withEtOAc (500 mL). The organic layer was washed twice with water, driedover sodium sulfate, filtered and concentrated to afford the titlecompound (2.6 g, 100%).

Step C: Preparation ofN-(methylsulfonyloxy)tetrahydrofuran-2-carbimidoyl chloride: A 500 mLround-bottomed flask was charged with tetrahydrofuran-2-carbonylchloride oxime (2.6 g, 17.4 mmol), methanesulfonyl chloride (1.4 mL,17.4 mmol), and Et₂O (200 mL). Triethylamine (2.4 mL, 17.4 mmol) wasadded dropwise over 1 minute and stirred at ambient temperature for 10minutes. The solids were filtered and the filtrate was concentrated. Theresidue was purified on silica gel (100% CH₂Cl₂) to afford the titlecompound (2.1 g, 53.07% yield).

Step D: Preparation of5-bromo-3-phenoxy-N-(3-(tetrahydrofuran-2-yl)-1,2,4-thiadiazol-5-yl)pyridin-2-amine:A 20 mL vial was charged withN-(methylsulfonyloxy)tetrahydrofuran-2-carbimidoyl chloride (129 mg,0.57 mmol), pyridine (0.137 mL, 1.7 mmol), NaSCN (45.9 mg, 0.57 mmol)and CH₃CN (4 mL). The reaction was heated to 40° C. for 40 minutes.5-bromo-3-phenoxypyridin-2-amine (100 mg, 0.38 mmol) was added and thereaction was heated to 50° C. overnight. The reaction was poured intosaturated aqueous NaHCO₃ and extracted with EtOAc. The organic layer wasdried with sodium sulfate, filtered and concentrated. The residue waspurified on silica gel (30% EtOAc in hexanes) to afford the titlecompound (121 mg, 76.5% yield) as a tan solid. ¹H NMR (d₆-DMSO) δ 12.22(s, 1H), 8.32 (d, 1H), 7.47 (d, 1H), 7.39 (m, 2H), 7.17 (m, 1H), 7.07(m, 2H), 3.98 (t, 1H), 3.83-3.68 (m, 3H), 3.53 (m, 1H), 2.19 (q, 2H).Mass spectrum (apci) m/z=419.1 (M+H).

By the procedures in Example 183, the following compounds were alsoprepared.

Example Structure Name Data 184

N-(5-bromo-3- phenoxypyridin-2-yl)- 3-methyl-1,2,4- thiadiazol-5-amine¹H NMR (CDCl₃) δ 9.10 (s, 1H), 8.20 (m, 1H), 7.45 (m, 2H), 7.28 (m, 1H),7.19 (d, 1H), 7.08 (m, 2H), 2.53 (s, 3H). Mass spectrum (apci) m/z =363.1, 365.0 (M + H). 185

N-(5-bromo-3- phenoxypyridin-2-yl)- 3-(piperidin-4-yl)-1,2,4-thiadiazol-5- amine dihydrochloride ¹H NMR (d₆-DMSO) δ 12.20 (s,1H), 8.66 (bs, 1H), 8.47 (bs, 1H), 8.31 (d, 1H), 7.46 (d, 1H), 7.40 (m,2H), 7.18 (t, 1H), 7.08 (d, 2H), 3.51 (s, 2H), 3.15-2.90 (m, 3H), 2.10(m, 2H), 1.88 (m, 2H). Mass spectrum (apci) m/z = 432.2 (M + H − 2HCl).186

N-(5-bromo-3- phenoxypyridin-2-yl)- 3-isobutyl-1,2,4- thiadiazol-5-amine¹H NMR (CDCl₃) δ 9.02 (s, 1H0, 8.21 (d, 1H), 7.45 (m, 2H), 7.28 (m, 1H),7.19 (d, 1H), 7.08 (m, 2H), 2.71 (d, 2H), 2.22 (m, 1H), 0.98 (d, 6H).Mass spectrum (apci) m/z = 405.1 (M + H). 187

N-(5-bromo-3- (phenylthio)pyridin-2- yl)-3-methyl-1,2,4-thiadiazol-5-amine ¹H NMR (CDCl₃) δ 9.30 (bs, 1H), 8.50 (d, 1H), 7.98(d, 1H), 7.30 (m, 3H), 7.20 (m, 2H), 2.51 (s, 3H). Mass spectrum (apci)m/z = 379.1, 381.0 (M + H). 188

N-(5-bromo-3- (phenylthio)pyridin-2- yl)-3-isopropyl-1,2,4-thiadiazol-5-amine hydrochloride ¹H NMR (CDCl₃) δ 9.30 (bs, 1H), 8.51(m, 1H), 7.96 (m, 1H), 7.30 (m, 3H), 7.20 (m, 2H), 3.14 (m, 1H), 1.35(d, 6H). Mass spectrum (apci) m/z = 407.1 (M + H − HCl). 189

N-(5-bromo-3-(4- fluorophenoxy)pyridin- 2-yl)-3-methyl-1,2,4-thiadiazol-5-amine ¹H NMR (CDCl₃) δ 9.04 (bs, 1H), 8.20 (d, 1H), 7.14(m, 3H), 7.07 (m, 2H), 2.54 (s, 3H). Mass spectrum (apci) m/z = 381.1,383.1 (M + H). 190

N-(5-bromo-3-(4- fluorophenoxy)pyridin- 2-yl)-3-isobutyl-1,2,4-thiadiazol-5-amine ¹H NMR (CDCl₃) δ 9.05 (bs, 1H), 8.21 (d, 1H), 7.14(m, 3H), 7.07 (m, 2H), 2.72 (d, 2H), 2.22 (m, 1H), 0.98 (d, 6H). Massspectrum (apci) m/z = 423.1, 425.2 (M + H). 191

tert-butyl 4-(5-(5- bromo-3-(4- fluorophenoxy)pyridin- 2-ylamino)-1,2,4-thiadiazol-3- yl)piperidine-1- carboxylate ¹H NMR (CDCl₃) δ 9.01 (bs,1H), 8.20 (d, 1H), 7.15 (m, 3H), 7.07 (m, 2H), 4.14 (m, 2H), 2.93 (m,3h), 2.04 (m, 2H), 1.81 (m, 2H), 1.46 (s, 9H). Mass spectrum (apci) m/z= 450.2 (M + H − Boc). 192

tert-butyl 4-((5-(5- bromo-3-(4- fluorophenoxy)pyridin-2-ylamino)-1,2,4- thiadiazol-3- yl)methyl)piperidin-1- carboxylate ¹HNMR (CDCl₃) δ 9.01 (bs, 1H), 8.21 (m, 1H), 7.15 (m, 3H), 7.08 (m, 2H),4.09 (m, 2H), 2.78 (d, 2H), 2.71 (m, 2H), 2.04 (m, 1H), 1.69 (m, 2H),1.45 (s, 9H), 1.24 (m, 2H). Mass spectrum (apci) m/z = 464.2 (M + H −Boc).

Example 1934-methyl-N-(3-(phenylthio)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-yl)thiazol-2-aminehydrochloride

Step A: Preparation of(6-(4-methylthiazol-2-ylamino)-5-(phenylthio)pyridin-3-vyl)(tetrahydro-2H-pyran-4-yl)methanolhydrochloride: A 10 mL round-bottomed flask was charged with5-bromo-N-(4-methylthiazol-2-yl)-3-(phenylthio)pyridin-2-amine (250 mg,0.661 mmol), THF (6 mL) and cooled to −78° C. and methyllithium (0.496mL, 0.793 mmol) was added. The reaction was stirred for 5 minutes andbutyllithium (0.317 mL, 0.793 mmol) was added. The reaction was stirredfor 10 minutes and tetrahydro-2H-pyran-4-carbaldehyde (151 mg, 1.32mmol) was added. The reaction was warmed to ambient temperature andpoured into saturated aqueous NH₄Cl and extracted with EtOAc (2×20 mL).The organic layer was dried with sodium sulfate, filtered andconcentrated. The residue was purified on silica gel (50% EtOAc inhexanes) to afford the title compound (217 mg, 73.0% yield) after HClsalt formation.

Step B: Preparation ofN-(4-methylthiazol-2-yl)-3-(phenylthio)-5-((tetrahydropyran-4-ylidene)methyl)pyridin-2-aminehydrochloride: A 10 mL round-bottomed flask was charged with(6-(4-methylthiazol-2-ylamino)-5-(phenylthio)pyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methanolhydrochloride (125 mg, 0.278 mmol), 4-methylbenzenesulfonic acid hydrate(5.28 mg, 0.0278 mmol), Toluene (5 mL) and heated to reflux in deanstark trap for 24 7 hours. The reaction was cooled to ambienttemperature and partitioned between saturated aqueous sodium bicarbonateand CH₂Cl₂. The organic layer was dried with sodium sulfate, filteredand concentrated. The residue was purified on silica gel (25% EtOAc inhexanes) to afford the title compound (42 mg, 35.0% yield) as after HClsalt formation. ¹H NMR (CDCl₃) δ 12.24 (bs, 1H), 8.18 (m, 1H), 7.71 (m,1H), 7.54 (m, 2H), 7.30 (m, 3H), 6.40 (s, 1H), 6.20 (s, 1H), 3.78 (t,2H), 3.65 (t, 2H), 2.45 (s, 3H), 2.42 (m, 4H). Mass spectrum (apci)m/z=396.2 (M+H—HCl).

Step C: Preparation ofN-(4-methylthiazol-2-yl)-3-(phenylthio)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-aminehydrochloride: Prepared according to the method of Example 44, Step C.¹H NMR (d₆-DMSO)S 8.26 (s, 1H), 7.85 (s, 1H), 7.35-7.19 (m, 5H), 6.82(s, 1H), 3.74 (m, 2H), 3.15 (t, 2H), 2.49 (d, 2H), 2.24 (s, 3H), 1.67(m, 1H), 1.38 (m, 2H), 1.12 (m, 2H). Mass spectrum (apci) m/z=398.3(M+H—HCl).

Example 194N-(5-(2-chloro-5-methoxyphenylthio)-3-phenoxypyridin-2-yl)-4-methylthiazol-2-aminehydrochloride

Step A: Preparation of 1,2-bis(2-chloro-5-methoxyphenyl)disulfane: To asolution of 2-bromo-1-chloro-4-methoxybenzene (4.42 g, 19.9 mmol) in THFstirring at −10° C. under nitrogen was added isopropylmagnesium chloride(9.9 mL, 19.9 mmol, 2M in THF). The reaction was allowed to warm toambient temperature stirred for 4 hours. The reaction was cooled to −40°C. and zinc(II) chloride (19.9 mL, 19.9 mmol, 1M in ether) was added andthe solution stirred for minutes. The reaction was cooled to −78° C. andsulfurothioyl dichloride (0.80 mL, 9.9 mmol) was added. After stirringfor 15 minutes at −78° C., saturated NH₄Cl was added and the mixture waswarmed to ambient temperature and extracted multiple times with EtOAc.The combined organic layers were dried with sodium sulfate, filtered,and concentrated to give a residue which was purified by silicachromatography (10% EtOAc in hexanes) to afford the title compound (1.52g, 21.9% yield).

Step B: Preparation of5-(2-chloro-5-methoxyphenylthio)-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-aminehydrochloride: Prepared according to the method of Example 8, using1,2-bis(2-chloro-5-methoxyphenyl)disulfane to afford the title compound(0.960 g, 56.5% yield) after HCl salt formation. ¹H NMR (d₆-DMSO) δ 8.26(m, 1H), 7.40 (m, 3H), 7.32 (m, H), 7.18 (t, 1H), 7.11 (d, 2H), 6.81(dd, 1H), 6.73 (s, 1H), 6.41 (d, 1H), 3.64 (s, 3H), 2.27. (s, 3H). Massspectrum (apci) m/z=456.3 (M+H—HCl).

Example 195(R)-4-methyl-N-(5-(5-methyl-6,7-dihydro-5H-cyclopenta(dipyrimidin-4-ylthio)-3-phenoxypyridin-2-yl)thiazol-2-aminedihydrochloride

Step A: Preparation of (2R)-ethyl2-methyl-5-(propan-2-ylidene)cyclopentanecarboxylate: To a 3 L roundbottom flask was added (r)-Pulegone (300 g, 1.97 mol), anhydrous NaHCO₃(82 g, 0.99 mol) and Ether (1.5 L). The mixture was cooled to −5° C.ice-salt bath under N₂. Then bromine (101 mL, 1.97 mol) was addeddropwise over 45 minutes. The mixture was filtered and carefully addeddropwise (addition is exothermic in nature) to NaOEt (20 wt %, 4.3 mol)cooled at 0° C. The reaction was allowed to stir with warming to ambienttemperature overnight. Then 1 L of 5% HCl and 300 mL of ether was added.The aqueous phase was extracted with ether and the combined organiclayers washed with brine, dried with MgSO₄ and concentrated. Theresulting brown oil diluted with EtOH was added to a warm solution ofsemicarbazide HCl (150 g, 1.3 mol), NaOAc (150 g, 1.8 mol) and H₂O (2 L)to give a brownish solution. The mixture was then refluxed for 3 hoursand stirred at ambient temperature overnight. The mixture was treatedwith 1 L of water and 500 mL of ether. The aqueous phase was extractedwith ether. The combined organic layers were dried with MgSO₄ andconcentrated to give a brown oil. The oil was subject to vacuumdistillation, and the title compound (247 g, 64% yield) was collected at73-76° C.

Step B: Preparation of (2R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate:The (2R)-ethyl 2-methyl-5-(propan-2-ylidene)cyclopentanecarboxylate (139g, 662 mmol) in EtOAc (900 mL) was cooled to −78° C. using a dryice-isopropanol bath. This mixture was subjected to ozonolysis until thereaction turn purple in color. Ozone generation ceased and the reactionremoved from the dry-ice bath. Oxygen was bubbled through the reactionuntil the reaction turned yellow. The reaction was concentrated and theresulting residue dissolved in 60 mL of glacial acetic acid. Thesolution was cooled to 0° C. and Zn dust was added portionwise over 30minutes. The reaction was then allowed to stir for 1 hour, then filteredthrough celite to remove the zinc. The acetic acid was neutralized to pH7 with aqueous NaOH and NaHCO₃ and extracted with ether. The organicswere dried with brine, MgSO₄ and concentrated to give the desiredmaterial as a brownish liquid. The material was passed through a silicaplug (eluting 8:1, hex/EtOAc) to remove polar impurities to afford thetitle compound (82 g, 73% yield).

Step C: Preparation of (R)-ethyl2-amino-5-methylcyclopent-1-enecarboxylate: To a solution of (R)-ethyl2-methyl-5-oxocyclopentanecarboxylate (106 g, 622 mmol) in 1.2 L MeOHwas added ammonium acetate (240 g, 3.1 mol). The reaction was stirredfor 20 hours and concentrated to remove MeOH. The resulting residue wasdissolved in CH₂Cl₂, washed with H₂O, brine, dried (Na₂SO₄), filteredand concentrated to give the title compound (102 g, 97% yield) as anorange oil.

Step D: Preparation of(R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol: A 2 L 3-neckround bottom flask equipped with a condenser, internal temperatureprobe, was charged with (R)-ethyl2-amino-5-methylcyclopent-1-enecarboxylate (185 g, 1093 mmol) andammonium formate (103.4 g, 1640 mmol) in formamide (400 mL) and toluene(200 mL). The reaction was heated to an internal temperature of 150° C.and stirred for 36 hours. The reaction was cooled and transferred to a 2L single next flask and excess formamide was removed by high vacuumdistillation. The resulting oil was dissolved in CH₂Cl₂ and washed withbrine. The combined aqueous layers were extracted with CH₂Cl₂. Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated to give the crude product as a brown semi solid which wastaken into the next step without any further purification.

Step E: Preparation of(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine: Thesolution of (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol(2.08 g, 13.9 mmol) in POCl₃ (10 ml) was refluxed for 2 hours. Aftercooling, the excess POCl₃ was evaporated and the residue was dissolvedin CH₂Cl₂ (50 ml) and was neutralized with saturated NaHCO₃. The aqueousphase was extracted with CH₂Cl₂. The organic phase was dried andconcentrated. The residue purified on silica gel (20% EtOAc in hexanes)to afford the title compound (1.0 g, 44% yield).

Step F: Preparation of(R)-5-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylthio)-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-aminedihydrochloride: Prepared according to the method of Example 127 using(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine to affordthe title compound (51.6 mg, 49.8% yield) after HCl salt formation. ¹HNMR (d₆-DMSO) δ 8.63 (m, 1H), 8.26 (m, 1H), 7.42 (m, 3H), 7.16 (m, 3H),6.75 (s, 1H), 3.29 (m, 1H), 3.03 (m, 1H), 2.80 (m, 1H), 2.28 (m, 4H),1.72 (m, 1H), 1.27 (d, 3H). Mass spectrum (apci) m/z=448.3 (M+H-2HCl).

Example 1963-(2-(3-phenoxy-5-(pyridin-4-ylthio)pyridin-2-ylamino)thiazol-4-yl)propanoicacid dihydrochloride

Prepared according to the method of Example 45 from Methyl3-(2-(3-phenoxy-5-(pyridin-4-ylthio)pyridin-2-ylamino)thiazol-4-yl)propanoate.¹H NMR (d₆-DMSO) δ 8.58 (m, 2H), 8.38 (m, 1H), 7.64 (m, 2H), 7.48 (m,1H), 7.43 (m, 2H), 7.18 (m, 3H), 6.78 (m, 1H), 2.86 (m, 2H), 2.71 (m,1H), 2.62 (m, 1H). Mass spectrum (apci) m/z=451.2 (M+H-2HCl).

Example 197N-(5-(3,5-dimethylisoxazolo[4,5-b]pyridin-7-ylthio)-3-phenoxypyridin-2-yl)-4-methylthiazol-2-aminedihydrochloride

Step A: Preparation of 3,5-dimethylisoxazolo[4,5-b]pyridine 4-oxide:3,5-dimethyl-4-nitroisoxazole (2.50 g, 17.6 mmol) in 25 mL EtOH wasdissolved. Piperidine (0.174 mL, 1.76 mmol) was added followed bypropionaldehyde (1.52 mL, 21.1 mmol). The solution was heated at 90° C.overnight. The solution was concentrated and chromatographed using EtOActo obtain the title compound (0.650 g, 22.5% yield).

Step B: Preparation of 7-chloro-3,5-dimethylisoxazol[4,5-b]pyridine:3,5-dimethylisoxazolo[4,5-b]pyridine 4-oxide (0.650 g, 3.96 mmol) inchloroform (5 mL), was added POCl₃ (1.45 mL, 15.8 mmol) and the mixturewas heated at 80° C. for 2 hours. The solution was cooled and pouredonto ice water. The solution was neutralized with saturated NaHCO₃ andthe solution was then extracted with EtOAc, dried, and concentrated. Thesolid was triturated with ether and filtered twice to obtain two cropsof the title compound (0.417 g, 57.7% yield).

Step C: Preparation of5-(3,5-dimethylisoxazolo[4,5-b]pyridin-7-ylthio)-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-aminedihydrochloride: Prepared according to the method of Example 127. ¹H NMR(d₆-DMSO) δ 8.39 (dd, 1H), 7.48 (dd, 1H), 7.39 (m, 3H), 7.15 (m, 3H),7.06 (d, 1H), 6.74 (s, 1H), 2.54 (m, 3H), 2.52 (m, 3H), 2.28 (s, 3H).Mass spectrum (apci) m/z=461.9 (M+H-2HCl).

Example 1981-(4-(2-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanonedihydrochloride

Step A: A 100 mL round-bottomed flask was charged with tert-butyl4-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate(1.6 g, 3.0 mmol), N-ethyl-N-isopropylpropan-2-amine (1.0 mL, 6.0 mmol),Xantphos (0.087 g, 0.15 mmol), and Dioxane (25 mL). Nitrogen was bubbledthrough the solution for 10 minutes. Methyl 3-mercaptopropanoate (0.40mL, 3.6 mmol) and Pd₂dba₃ (0.068 g, 0.075 mmol) were added and thereaction was plunged into a 95° C. oil bath for 6 hours. The reactionwas cooled to room temperature and the solids filtered through celiteand concentrated. The residue was purified on silica (30% EtOAc inhexanes) to afford tert-butyl4-(2-(5-(3-methoxy-3-oxopropylthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate(1.4 g; 81.48% yield) as a white foam.

Step B: A 25 mL round-bottomed flask was charged with tert-butyl4-(2-(5-(3-methoxy-3-oxopropylthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate(500 mg, 0.876 mmol), 7-chlorothieno[3,2-b]pyridine (178 mg, 1.05 mmol),and DMSO (8 mL). Nitrogen was bubbled through the solution for 10minutes. Potassium 2-methylpropan-2-olate (295 mg, 2.63 mmol) was addedand stirred at room temperature for 30 minutes. The reaction was pouredinto saturated aqueous NH₄Cl and extracted with EtOAc (2×20 mL). Theorganic layer was dried with sodium sulfate, filtered and concentrated.The residue was purified on silica (50% EtOAc in hexanes) to affordtert-butyl4-(2-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate.

Step C: tert-Butyl4-(2-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylatewas dissolved in 1:1CH₂Cl₂:methanol and 4N HCl in dioxane added andstirred for 1 hour at room temperature. The reaction was concentratedand the residue was partitioned between CH₂Cl₂ and saturated aqueoussodium bicarbonate. The organic layer was dried over sodium sulfate,filtered and concentrated to afford3-phenoxy-N-(4-(piperidin-4-yl)thiazol-2-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine(238 mg, 52.5% yield over 2 steps) as a white solid

Step D: A 20 mL vial was charged with3-phenoxy-N-(4-(piperidin-4-yl)thiazol-2-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine(80 mg, 0.15 mmol), triethylamine (0.043 mL, 0.31 mmol), and THF (2 mL).Acetyl chloride (0.011 mL, 0.15 mmol) was added and stirred at ambienttemperature for 10 minutes. The reaction was poured into saturatedaqueous NaHCO₃ and extracted with EtOAc. The organic layer was driedwith sodium sulfate, filtered and concentrated. The residue was purifiedon silica gel (5 to 10% methanol in EtOAc) to afford the title compound(35.1 mg, 35.9% yield) as a yellow solid after HCl salt formation. ¹HNMR (d₆-DMSO) δ 8.65 (d, 1H), 8.48 (d, 1H), 8.46 (d, 1H), 7.77 (d, 1H),7.54 (d, 1H), 7.41 (m, 2H), 7.18 (m; 4H), 6.82 (s, 1H), 4.43 (m, 1H),3.88 (m, 1H), 3.14 (m, 1H), 2.89 (m, 1H), 2.64 (m, 1H), 2.01 (s, 3H),1.96 (m, 2H), 1.58 (m, 1H), 1.45 (m, 1H). Mass spectrum (apci) m/z=560.4(M+H-2HCl).

The following compounds were also prepared according to the procedure ofExample 198, Step D.

Example Structure Name Data 199

1-(4-(5-(5-bromo-3- phenoxypyridin-2- ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1- yl)ethanone ¹H NMR (CDCl₃) δ 9.01 (s, 1H), 8.21 (d,1H), 7.46 (m, 2H), 7.30 (m, 1h), 7.19 (d, 1H), 7.09 (m, 2H), 4.57 (m,1H), 3.89 (m, 1h), 3.22 (m, 1H), 3.07 (m, 1H), 2.83 (m, 1H), 2.11 (m,5H), 1.95-1.75 (m, 2H). Mass spectrum (apci) m/z = 476.2 (M + H). 200

1-(4-(5-(3-phenoxy-5- (thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)- 1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone dihydrochloride ¹H NMR (d₆-DMSO) δ 12.48 (bs,1H), 8.56 (d, 1H), 8.53 (d, 1H), 8.28 (d, 1H), 7.65 (d, 1H), 7.57 (d,1H), 7.40 (m, 2H), 7.18 (m, 1H), 7.14 (m, 2H), 7.07 (d, 1H), 4.32 (m,1H), 3.20 (m, 1H), 3.07 (m, 1H), 2.77 (m, 1H), 2.01 (m, 5H), 1.73 (m,1H), 1.59 (m, 1H). Mass spectrum (apci) m/z = 561.3 (M + H − 2HCl). 201

1-(4-(5-(3-(phenylthio)-5- (thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)- 1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone hydrochloride ¹H NMR (d₆-DMSO) δ 8.72 (s,1H), 8.61 (d, 1H), 8.38 (d, 1H), 7.86 (bs, 1H), 7.71 (d, 1H), 7.36 (m,4H), 7.31 (m, 1H), 7.09 (d, 1H), 4.33 (m, 1H), 3.85 (m, 1H), 3.18 (m,1H), 3.05 (m, 1H), 2.74 (m, 1H) 2.01 (m, 5H), 1.73 (m, 1H), 1.58 (m,1H). Mass spectrum (apci) m/z = 577.3 (M + H − HCl). 202

1-(4-(2-(3-(phenylthio)-5- (pyridin-2-ylthio)pyridin-2-ylamino)thiazol-4- yl)piperidin-1-yl)ethanone hydrochloride ¹H NMR(d₆-DMSO) δ 8.46 (m, 1H), 8.36 (m, 1H), 7.68 (t, 2H), 7.39 (m, 6H), 7.17(m, 1H), 7.09 (d, 1H), 6.73 (s, 1H), 4.44 (m, 1H), 3.89 (m, 1H), 3.12(m, 1H), 2.87 (m, 1H), 2.62 (m, 1H), 2.01 (m, 5H), 1.58 (m, 1H), 1.43(m, 1H). Mass spectrum (apci) m/z = 520.3 (M + H − HCl). 203

methyl 4-(2-(3- (phenylthio)-5-(pyridin-2- ylthio)pyridin-2-ylamino)thiazol-4- yl)piperidine-1- carboxylate hydrochloride ¹H NMR(d₆-DMSO) δ 8.43 (s, 1H), 8.36 (m, 1H), 7.66 (m, 2H), 7.39 (m, 5H), 7.15(m, 1H), 7.06 (m, 1H), 6.68 (s, 1H), 4.04 (m, 2H), 3.60 (s, 3H),2.95-2.75 (m, 3H), 1.93 (m, 2H), 1.50 (m, 2H). Mass spectrum (apci) m/z= 536.2 (M + H − HCl). 204

1-(4-(2-(3-(phenylthio)-5- (thieno[3,2-b]pyridin-7- ylthio)pyridin-2-ylamino)thiazol-4- yl)piperidin-1-yl)ethanone dihydrochloride ¹H NMR(d₆-DMSO) δ 8.57 (d, 1H), 8.49 (bs, 1H), 8.32 (d, 1H), 7.66 (d, 1H),7.39 (m, 6H), 6.98 (d, 1H), 6.61 (s, 1H), 4.45 (m, 1H), 3.88 (m, 1H),3.11 (m, 1H), 2.82 (m, 1H), 2.60 (m, 1H), 2.02 (s, 3H), 1.95 (m, 2H),1.57 (m, 1H), 1.43 (m, 1H). Mass spectrum (apci) m/z = 576.3 (M + H −2HCl). 205

4-(1- (methylsulfonyl)piperidin- 4-yl)-N-(3-(phenylthio)-5-(thieno[3,2-b]pyridin-7- ylthio)pyridin-2- yl)thiazol-2-aminedihydrochloride ¹H NMR (d₆-DMSO) δ 8.59 (dd, 1H), 8.51 (s, 1H), 8.36(dd, 1H), 7.69 (dd, 1H), 7.40 (m, 6h), 7.02 (d, 1H), 6.67 (s, 1H), 3.64(m, 2H), 2.89 (s, 3H), 2.81 (m, 2H), 2.70 (m, 1H), 2.07 (m, 2H), 1.65(m, 2H). Mass spectrum (apci) m/z = 612.2 (M + H − 2HCl). 206

2-(dimethylamino)-1-(4- (2-(3-(phenylthio)-5- (thieno[3,2-b]pyridin-7-ylthio)pyridin-2- ylamino)thiazol-4- yl)piperidin-1-yl)ethanonetrihydrochloride ¹H NMR (d₆-DMSO) δ 9.61 (s, 1H), 8.59 (d, 1H), 8.52 (s,1H), 8.35 (d, 1H), 7.70 (d, 1H), 7.39 (m, 6H), 7.01 (d, 1H), 6.65 (s,1H), 4.44 (m, 1H), 4.31 (m, 2H), 3.68 (m, 1H), 3.16 (m, 1H), 2.90 (m,2H), 2.82 (m, 6H), 2.03 (m, 2H), 1.62 (m, 1H), 1.50 (m, 1H). Massspectrum (apci) m/z = 619.2 (M + H − 3HCl). 207

1-(4-(5-(3-(4- fluorophenoxy)-5-(5- methylpyrazolo[1,5- a]pyrimidin-7-ylthio)pyridin-2-ylamino)- 1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone dihydrochloride ¹H NMR (d₆-DMSO) δ 12.51 (s,1H), 8.53 (d, 1H), 8.20 (d, 1H), 7.65 (d, 1H), 7.26 (m, 4H), 6.58 (d,1H), 6.31 (s, 1H), 4.33 (m, 1H), 3.85 (m, 1H), 3.20 (m, 1H), 3.08 (m,1H), 2.78 (m, 1H), 2.41 (s, 3H), 2.02 (m, 5H), 1.74 (m, 1H), 1.60 (m,1H). Mass spectrum (apci) m/z = 577.2 (M + H − 2HCl). 208

1-(4-(5-(3-(4- fluorophenoxy)-5- (thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)- 1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone dihydrochloride ¹H NMR (d₆-DMSO) δ 12.49 (bs,1H), 8.57 (d, 1H), 8.52 (d, 1H), 8.32 (d, 1H), 7.67 (d, 1H), 7.58 (d,1H), 7.21 (m, 4H), 7.08 (d, 1H), 4.32 (m, 1H), 3.85 (m, 1H), 3.20 (m,1H), 3.07 (m, 1H), 2.77 (m, 1H), 2.01 (m, 5H), 1.74 (m, 1H), 1.59 (m,1H). Mass spectrum (apci) m/z = 579.2 (M + H − 2HCl). 209

N-(3-(4-fluorophenoxy)-5- (thieno[3,2-b]pyridin-7-ylthio)pyridin-2-yl)-3-(1- (methylsulfonyl)piperidin-4-yl)-1,2,4-thiadiazol-5- amine dihydrochloride ¹H NMR (d₆-DMSO) δ 12.53(bs, 1H), 8.61 (d, 1H), 8.54 (d, 1H), 8.39 (d, 1H), 7.72 (d, 1H), 7.61(d, 1H), 7.23 (m, 4H), 7.14 (d, 1H), 3.60 (m, 2H), 2.92 (m, 2H), 2.88(s, 3H), 2.14 (m, 2H), 1.82 (m, 2H). Mass spectrum (apci) m/z = 615.2(M + H − 2HCl). 210

2-(dimethylamino)-1-(4- (5-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7- ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3- yl)piperidin-1-yl)ethanone trihydrochloride ¹H NMR(d₆-DMSO) δ 12.49 (bs, 1H), 9.61 (bs, 1H), 8.58 (d, 1H), 8.52 (d, 1H),8.33 (d, 1H), 7.69 (d, 1H), 7.59 (d, 1H), 7.23 (m, 4H), 7.08 (d, 1H),4.32 (m, 2H), 3.65 (m, 1H), 3.19 (m, 2H), 2.96 (m, 1H), 2.82 (m, 7H),2.09 (m, 2H), 1.82 (m, 1H), 1.65 (m, 1H). Mass spectrum (apci) m/z =622.2 (M + H − 3HCl).

Example 2113-(phenylthio)-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-aminedihydrochloride

Step A: Preparation of tert-butyl4-(2-(5-(3-methoxy-3-oxopropylthio)-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate:Prepared according to the method of Example 13 from tert-butyl4-(2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate.

Step B: Preparation of tert-butyl4-(5-(3-(phenylthio)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylatePrepared according to the method of Example 127.

Step C: Preparation of3-(phenylthio)-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-aminedihydrochloride: Tert-butyl4-(5-(3-(phenylthio)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylatewas dissolved in 1:1CH₂Cl₂:methanol (4 mL) and 4N HCl in dioxane added(2 mL) and stirred at ambient temperature for 1 hour. The solvent wasremoved and placed on high vacuum to afford the title compound (100 mg,89.6% yield) as a yellow solid. ¹H NMR (d₆-DMSO)S 8.70 (m, 2H), 8.20 (m,3H), 7.95 (m, 1H), 7.40 (m, 5H), 3.80-3.05 (m, 9H). Mass spectrum (apci)m/z=535.2 (M+H-3HCl).

Using the procedure in Example 211, steps A and B or steps A-C, thefollowing compounds were prepared.

Example Structure Name Data 212

N-(3-(phenylthio)-5- (pyridin-2- ylthio)pyridin-2-yl)- 4-(piperidin-4-yl)thiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ 9.06 (m, 1H), 8.84(m, 1H), 8.48 (s, 1H), 8.36 (m, 1H), 7.80 (bs, 1H), 7.68 (m, 1H), 7.39(m, 4H), 7.32 (m, 1H), 7.17 (m, 1H), 7.10 (d, 1H), 6.77 (s, 1H), 3.69(m, 1H), 3.49 (m, 1H), 3.31 (m, 1H), 2.95 (m, 3H), 2.12 (m, 2H), 1.80(m, 2H). Mass spectrum (apci) m/z = 478.3 (M + H − 2HCl). 213

tert-butyl 4-(2-(3- (phenylthio)-5- (thieno[3,2- b]pyridin-7-ylthio)pyridin-2- ylamino)thiazol-4- yl)piperidine-1- carboxylate ¹H NMR(CDCl₃) δ 9.18 (s, 1H), 8.58 (d, 1H), 8.48 (d, 1H), 7.99 (d, 1H), 7.74(d, 1H), 7.56 (d, 1H), 7.31-7.17 (m, 4H), 6.79 (d, 1H), 6.49 (s, 1H),4.20 (m, 2H), 2.80 (m, 3H), 2.00 (m, 2H), 1.65-1.51 (m, 2H), 1.47 (s,9H). Mass spectrum (apci) m/z = 534.3 (M + H − Boc). 214

tert-butyl 4-(5-(3-(4- fluorophenoxy)-5- (5- methylpyrazolo[1,5-a]pyrimidin-7- ylthio)pyridin-2- ylamino)-1,2,4- thiadiazol-3-yl)piperidine-1- carboxylate ¹H NMR (CDCl₃) δ 9.26 (s, 1H), 8.43 (d,1H), 8.11 (d, 1H), 7.12 (m, 4H), 6.56 (d, 1H), 5.90 (s, 1h), 4.17 (m,2H), 3.02 (m, 1H), 2.92 (m, 2H), 2.45 (s, 3H), 2.07 (m, 2H), 1.84 (m,2H), 1.48 (s, 9H). Mass spectrum (apci) m/z = 535.2 (M + H − Boc).

Example 215 Sodium4-(6-(4-methylthiazol-2-ylamino)-5-phenoxyvpyridin-3-ylthio)benzoate

Step A: Preparation of methyl4-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)benzoate:Prepared according to the method of Example 127 from methyl3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate.

Step B: Preparation of4-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)benzoic acid:Prepared according to the method of Example 45 to afford the titlecompound (10.3 mg, 38.0% yield) as a white solid. ¹H NMR (d₆-DMSO) δ8.26 (m, 1H), 7.82 (m, 2H), 7.39 (m, 2H), 7.28 (m, 1H), 7.18 (m, 3H),7.10 (m, 2H), 6.65 (s, 1H), 2.25 (s, 3H). Mass spectrum (apci) m/z=436.3(M+H—Na).

Example Structure Name Data 216

3-methyl-7-(6- (4- phenethylthiazol- 2-ylamino)-5- phenoxypyridin- 3-ylthio)thieno[3,2- b]pyridine-6- carboxylic acid ¹H NMR (d₆-DMSO) δ11.20 (bs, 1H), 8.94 (s, 1H), 8.34 (m, 1H), 7.77 (s, 1H), 7.33-7.14 (m,9H), 7.08 (t, 1H), 6.95 (d, 1H), 6.68 (s, 1H), 2.98-2.83 (m, 4H), 2.36(s, 3H). Mass spectrum (apci) m/z = 597.2 (M + H). 217

3-methyl-7-(6- (4-methylthiazol- 2-ylamino)-5- phenoxypyridin- 3-ylthio)thieno[3,2- b]pyridine-6- carboxylic acid ¹H NMR (d₆-DMSO) δ 8.98(s, 1H), 8.36 (d, 1H), 7.87 (s, 1H), 7.40-7.05 (m, 4H), 6.95 (m, 2H),6.65 (bs, 1H), 2.38 (s, 3H), 2.24 (s, 3H). Mass spectrum (apci) m/z =507.1 (M + H).

Example 218N-(5-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-ylthio)-3-phenoxypyridin-2-yl)-4-methylthiazol-2-aminetrihydrochloride

Step A: Preparation of ethyl 5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylateN-oxide: mCPBA (7.3 g, 30 mmol) was added into a solution of ethyl5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate (5 g, 26 mmol) in CH₂Cl₂(200 mL) and stirred for 2 hours. The reaction was poured into water andextracted with CH₂Cl₂. The organic layer was washed with aqueous sodiumbisulfate, NaHCO₃ and brine, dried with Na₂SO₄, filtered andconcentrated to afford the title compound (4 g, 74% yield) as a whitesolid.

Step B: Preparation of ethyl4-chloro-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate: POCl₃ (20 mL, 218mmol) was added into ethyl 5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylateN-oxide (1 g, 4.80 mmol) and heated to 35° C. for 12 hours and 50° C.for another 5 hours. The solvent was evaporated and poured into water.The material was extracted with CH₂Cl₂, washed with NaHCO₃ and brine,dried with Na₂SO₄, filtered and concentrated. The residue was purifiedon silica gel to afford the title compound (0.5 g, 45.9% yield).

Step C: Preparation of5-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-ylthio)-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-aminetrihydrochloride: A 10 mL round-bottomed flask was charged with methyl3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate(65 mg, 0.16 mmol), ethyl4-chloro-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate (55 mg, 0.24 mmol),and DMSO (2 mL). The reaction was bubbled through with nitrogen andpotassium 2-methylpropan-2-olate (54 mg, 0.49 mmol) was added andstirred at ambient temperature for 30 minutes. The reaction was pouredinto saturated aqueous NH₄Cl and extracted with EtOAc. The organic layerwas dried with sodium sulfate, filtered and concentrated. The residuewas purified on silica gel (50% EtOAc in hexanes) to afford a residuethat was dissolved in methanol, KOH (xs) and water (0.5 mL) added andheated to 60° C. over the weekend. The reaction was poured intosaturated aqueous NH₄Cl and extracted with EtOAc. The organic layer wasdried with sodium sulfate, filtered and concentrated. The residue waspurified on silica gel (100% EtOAc to 20% methanol in CH₂Cl₂ with 0.2%ammonia) to afford the title compound (29 mg, 33% yield) as a yellowsolid after HCl salt formation. ¹H NMR (d₆-DMSO)S 10.12 (bs, 2H), 8.34(d, 1H), 8.31 (d, 1H), 7.42 (m, 2H), 7.36 (d, 1H), 7.17 (m, 3H), 6.84(d, 1H), 6.76 (s, 1H), 4.47 (m, 4H), 2.28 (s, 3H). Mass spectrum (apci)m/z=434.2 (M+H-3HCl).

Example 219N-(4-methylthiazol-2-yl)-3-phenoxy-5-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylthio)pyridin-2-aminetrihydrochloride

Step A: Preparation of tert-butyl4-chloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate: A mixtureof PPh₃ (81.4 g, 310 mmol) and N-chlorosuccinimide (41.4 g, 310 mmol) indioxane (850 mL) was stirred at ambient temperature for 30 minutes. Tothis suspension was added tert-butyl4-hydroxy-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate and themixture stirred at 50° C. for 18 hours. The mixture was subsequentlytreated with triethylamine (25 mL, 183 mmol) and the resulting brownsolution concentrated. The black oil was dry packed onto silica gel andpurified by chromatography eluting with 15-20% EtOAc/Hexanes to give thetitle compound as a yellow gum.

Step B: Preparation of affordN-(4-methylthiazol-2-yl)-3-phenoxy-5-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylthio)pyridin-2-aminetrihydrochloride: Prepared according to the method of Example 218, StepB. ¹H NMR (d₆-DMSO) δ 9.56 (bs, 2H), 8.75 (s, 1H), 8.24 (d, 1H), 7.43(m, 2H), 7.34 (m, 1H), 7.15 (m, 3H), 6.70 (s, 1H), 4.21 (m, 2H), 3.04(m, 2H), 2.26 (s, 3H). Mass spectrum (apci) m/z=449.2 (M+H-3HCl).

Example 2201-(4-((5-(3-(4-fluorophenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)methyl)piperidin-1-yl)ethanonedihydrochloride

Step A: Preparation of tert-butyl4-((5-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)methyl)piperidine-1-carboxylate:Prepared according to the method of Example 127.

Step B: Preparation of3-(4-fluorophenoxy)-N-(3-(piperidin-4-ylmethyl)-1,2,4-thiadiazol-5-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-aminetrihydrochloride: Prepared according to the method of Example 196, stepC.

Step C: Preparation of1-(4-((5-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)methyl)piperidin-1-yl)ethanonedihydrochloride: Prepared according to the method of Example 198. ¹H NMR(d₆-DMSO) δ 12.47 (bs, 1H), 8.57 (d, 1H), 8.51 (d, 1H), 8.33 (d, 1H),7.68 (d, 1H), 7.57 (d, 1H), 7.23 (m, 4H), 7.08 (d, 1h), 4.34 (m, 1H),3.78 (m, 1H), 2.98 (t, 1H), 2.72 (d, 2H), 2.09 (m, 1H), 1.97 (s, 3H),1.65 (m, 2H), 1.18 (m, 1H), 1.05 (m, 1H). Mass spectrum (apci) m/z=593.2(M+H-2HCl).

The following compounds were prepared according to the method of Example220.

Example Structure Name Data 221

1-(4-(5-(3-(4- fluorophenoxy)-5- (3-methylisoxazolo [5,4-b]pyridin-4-ylthio)pyridin-2- ylamino)-1,2,4- thiadiazol-3- yl)piperidin-1-yl)ethanone hydrochloride ¹H NMR (d₆-DMSO) δ 12.48 (bs, 1H), 8.49 (d,1H), 8.32 (d, 1H), 7.54 (m, 1H), 7.25 (m, 4H), 6.75 (d, 1H), 4.32 (m,1H), 3.85 (m, 1H), 3.20 (m, 1H), 3.07 (m, 1H), 2.77 (m, 1H), 2.69 (s,3H), 2.02 (m, 5H), 1.74 (m, 1H), 1.60 (m, 1H). Mass spectrum (esi) m/z =578.1 (M + H − HCl). 222

2-(dimethylamino)- 1-(4-(5-(3-(4- fluorophenoxy)-5- (3-methylisoxazolo[5,4-b]pyridin-4- ylthio)pyridin-2- ylamino)-1,2,4- thiadiazol-3-yl)piperidin-1- yl)ethanone dihydrochloride ¹H NMR (d₆-DMSO) δ 12.48(bs, 1H), 9.54 (bs, 1H), 8.49 (d, 1H), 8.32 (d, 1H), 7.55 (d, 1H), 7.25(m, 4H), 6.74 (d, 1H), 4.32 (m, 3H), 3.65 (m, 1H), 3.20 (m, 2H), 2.96(m, 1H), 2.82 (d, 6H), 2.70 (s, 3H), 2.09 (m, 2H), 1.82 (m, 1H), 1.65(m, 1H). Mass spectrum (esi) m/z = 621.1 (M + H − 2HCl)

Example 223 tert-Butyl4-(5-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate

Step A: Preparation of tert-butyl4-(5-(5-bromo-3-phenoxypyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate:Prepared according to the method of Example 183 step D.

Step B: Preparation of tert-butyl4-(5-(5-(3-methoxy-3-oxopropylthio)-3-phenoxypyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate:Prepared according to the method of Example 13.

Step C: Preparation of tert-butyl4-(5-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate:Prepared according to the method of Example 127. ¹H NMR (CDCl₃) δ 9.18(s, 1H), 8.48 (d, 1H), 8.37 (d, 1H), 7.79 (d, 1H), 7.55 (d, 1H), 7.40(m, 2H), 7.24 (m, 2H), 7.06 (m, 2H), 6.77 (d, 1H), 4.16 (m, 2H), 3.00(m, 1H), 2.91 (m, 2H), 2.05 (m, 2H), 1.83 (m, 2H), 1.47 (s, 9H). Massspectrum (esi) m/z=519.2 (M+H-Boc).

Example 224N-(5-((3-methoxypyridin-2-yl)methylthio)-3-phenoxypyridin-2-yl)-4-methylthiazol-2-aminehydrochloride

Placed2-((6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)methyl)pyridine-3-ol(prepared in Example 69) (0.180 g, 0.426 mmol) in DMF (5 mL) and cooledto 0° C. Sodium hydride (0.0307 g, 1.28 mmol) was added and stirred for10 minutes then MeI (0.0605 g, 0.426 mmol) was added stirred at ambienttemperature for 30 minutes. Added water and extracted with CH₂Cl₂. Theorganic layer was concentrated and purified by silica gel. The productwas still impure. Mixture was purified by medium pressure reverse phasefollowed by two high pressure reverse phase purifications. Combined allclean fractions' then dissolved in CH₂Cl₂ and added HCl in ether, thenconcentrated to give the title compound (0.0085 g, 4.22% yield). ¹H NMR(d₆-DMSO) δ 8.14 (m, 1H), 8.10 (d, 1H), 7.65 (m, 1H), 7.55 (m, 1H),7.34-7.27 (m, 3H), 7.03 (m, 1H), 6.85 (d, 2H), 6.36 (s, 1H), 4.24 (s,2H), 3.17 (s, 3H), 2.18 (s, 3H).

Example 2254-methyl-N-(3-phenoxy-5-(piperidin-4-yl(pyridin-2-yl)methylthio)pyridin-2-yl)thiazol-2-aminetris(2,2,2-trifluoroacetate)

Step A: Preparation of give tert-butyl4-(hydroxy(pyridin-2-yl)methyl)piperidine-1-carboxylate: Placed2-bromopyridine (0.833 g, 5.27 mmol) in THF (25 mL) and cooled to −78°C. Butyllithium (2.11 mL, 5.27 mmol) was slowly added and stirred for 5minutes. Dissolved tert-butyl 4-formylpiperidine-1-carboxylate (0.500 g,2.34 mmol) in THF (3 mL) and added slowly to the above solution thenstirred at −78° C. for 30 minutes. Added ammonium chloride and extractedwith CH₂Cl₂. Concentrated and purified by silica gel to give the titlecompound (0.229 g, 33.4% yield)

Step B: Preparation of tert-butyl4-((methylsulfonyloxy)(pyridin-2-yl)methyl)piperidine-1-carboxylate:Placed 2-bromopyridine (0.833 g, 5.27 mmol) in THF (25 mL) and cooled to−78° C. Slowly added butyl lithium (2.11 mL, 5.27 mmol) and stirred for5 min. Dissolved tert-butyl 4-formylpiperidine-1-carboxylate (0.500 g,2.34 mmol) in THF (3 mL) and added slowly to the above solution andstirred at −78° C. for 30 min. Added ammonium chloride and extractedwith CH₂Cl₂. Concentrated and purified by silica gel to give the titlecompound (0.229 g, 33.4% yield)

Step C: Preparation of gave tert-butyl4-((6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)(pyridin-2-yl)methyl)piperidine-1-carboxylate:Prepared according to the method of Example 16.

Step D: Preparation of4-methyl-N-(3-phenoxy-5-(piperidin-4-yl(pyridin-2-yl)methylthio)pyridin-2-yl)thiazol-2-aminetris(2,2,2-trifluoroacetate): Placed Me₂S (0.0072 g, 0.12 mmol) inTrifluoroacetic acid (10 mL) followed by tert-butyl4-((6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)(pyridin-2-yl)methyl)piperidine-1-carboxylate(0.068 g, 0.12 mmol) stirred at ambient temperature for 30 minutes, thenconcentrated to give the title compound (0.086 g, 90% yield). ¹H NMR(d₆-DMSO) δ 8.52 (bs, 1H), 8.42 (m, 1H), 8.17 (bs, 1H), 8.00 (d, 1H),7.70 (dt, 1H), 7.41 (t, 2H), 7.25-7.16 (m, 3H), 6.92 (d, 2H), 6.90 (s,1H), 6.63 (s, 1H), 4.22 (d, 1H), 3.32 (d, 1H), 3.17 (d, 1H), 2.98-2.74(m, 2H), 2.30 (m, 2H), 2.23 (s, 3H), 1.45 (m, 2H), 1.30 (m, 1H).

The following compounds were also made according to the procedure ofExample 225.

Example R′ R″ Name NMR 226

H 4-methyl-N-(3- phenoxy-5-(piperidin- 4-yl(pyrazin-2-yl)methylthio)pyridin- 2-yl)thiazol-2-amine bis(2,2,2- trifluoroacetate)¹H NMR (d₆-DMSO) δ 8.53-8.43 (m, 3H), 8.16 (m, 1H), 7.98 (s, 1H), 7.42(t, 2H), 7.19 (t, 1H), 6.92 (d, 2H), 6.63 (s, 1H), 4.34 (d, 1H), 3.33(d, 1H), 3.17 (d, 1H), 2.97-2.75 (m, 2H), 2.33 (m, 2H), 2.23 (s, 3H),1.47 (m, 2H), 1.28 (m, 1H) 227

H 4-methyl-N-(3- phenoxy-5-(piperidin- 4-yl(pyrimidin-2-yl)methylthio)pyridin- 2-yl)thiazol-2-amine bis(2,2,2- trifluoroacetate)¹H NMR (d₆-DMSO) δ 8.67 (d, 2H), 8.50 (m, 1H), 8.16 (m, 1H), 7.98 (d,1H), 7.43 (t, 2H), 7.33 (t, 1H), 7.20 (t, 1H), 6.97 (d, 2H), 6.90 (d,1H), 6.63 (s, 1H), 4.15 (d, 1H), 3.34 (d, 1H), 3.16 (d, 1H), 2.98-2.75(m, 2H), 2.35 (m, 2H), 2.23 (s, 3H), 1.60-1.23 (m, 3H) 228

BOC tert-butyl 4-((3- chloropyridin-2-yl)(6- (4-methylthiazol-2-ylamino)-5- phenoxypyridin-3- ylthio)methyl) piperidine-1- carboxylate¹H NMR (d₆-DMSO) δ 10.85 (bs, 1H), 8.42 (m, 1H), 7.89 (m, 1H), 7.81 (d,1H), 7.43 (t, 2H), 7.23 (m, 2H), 6.97 (d, 2H), 6.78 (m, 1H), 6.61 (s,1H), 4.40 (d, 1H), 4.01 (m, 1H), 3.80 (m, 1H), 2.70 (m, 1H), 2.23 (m,5H), 1.32 (s, 9H), 1.27-1.11 (m, 3H), 0.94 (m, 1H) 229

H N-(5-((3- chloropyridin-2- yl)(piperidin-4- yl)methylthio)-3-phenoxypyridin-2-yl)- 4-methylthiazol-2- amine bis(2,2,2-trifluoroacetate) ¹H NMR (d₆-DMSO) δ 8.55 (d, 1H), 8.41 (dd, 1H), 8.15(m, 1H), 7.95 (d, 1H), 7.85 (dd, 1H), 7.44 (t, 2H), 7.23 (dd, 1H), 7.21(t, 1H), 6.97 (d, 2H), 6.76 (d, 1H), 6.64 (s, 1H), 4.39 (d, 1H), 3.35(d, 1H), 3.14 (d, 1H), 2.93 (m, 1H), 2.80 (m, 1H), 2.40 (m, 2H), 2.24(s, 3H), 1.51 (m, 1H), 1.37 (m, 1H), 1.25 (m, 1H)

Example 230N-(2-(dimethylamino)ethyl)-3-(2-(4-isobutylthiazol-2-ylamino)-5-(pyrimidin-2-ylthio)pyridin-3-yloxy)benzamidedihydrochloride

Step A: Preparation of ethyl 3-(2-aminopyridin-3-yloxy)benzoatehydrochloride: Placed ethyl 3-(2-aminopyridin-3-yloxy)-4-chlorobenzoate(prepared according to Example 39, Step B; 8.96 g, 30.6 mmol) andPd(OH)₂/C (0.86 g, 6.2 mmol) in EtOH (200 mL) and placed under balloonhydrogen pressure for 18 hours. The reaction mixture was transferred toa Parr bottle and the pressure was increased to 30 psi for severalhours, and then the hydrogen pressure was increased to 50 psi for 2 moredays. The reaction mixture was filtered though a plug of celite andconcentrated to give the title compound e (8.3 g, 92.04% yield).

Step B: Preparation of ethyl 3-(2-amino-5-bromopyridin-3-yloxy)benzoate:Prepared according to the method of Example 10, Step B.

Step C: Preparation of ethyl3-(5-bromo-2-(3-(4-chlorobenzoyl)thioureido) pyridine-3-yloxy)benzoate:Prepared according to the method of Example 39, Step D.

Step D: Preparation of ethyl3-(5-bromo-2-thioureidopyridin-3-yloxy)benzoate: Prepared according tothe method of Example 39, Step E.

Step E: Preparation of3-(5-bromo-2-(4-isobutylthiazol-2-ylamino)pyridine-3-yloxy)benzoate:Prepared according to the method of Example 39, Step F.

Step F: Preparation of ethyl3-(2-(4-isobutylthiazol-2-ylamino)-5-(3-methoxy-3-oxopropylthio)pyridine-3-yloxy)benzoate:Prepared according to the method of Example 13.

Step G: Preparation of ethyl3-(2-(4-isobutylthiazol-2-ylamino)-5-(pyrimidin-2-ylthio)pyridine-3-yloxy)benzoate:Prepared according to the method of Example 127.

Step H: Preparation of3-(2-(4-isobutylthiazol-2-ylamino)-5-(pyrimidin-2-ylthio)pyridine-3-yloxy)benzoicacid: Prepared according to the method of Example 70, Step B.

Step I: Preparation ofN-(2-(dimethylamino)ethyl)-3-(2-(4-isobutylthiazol-2-ylamino)-5-(pyrimidin-2-ylthio)pyridine-3-yloxy)benzamidedihydrochloride: Prepared according to the method of Example 7.

Example 2312-(4-((6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)(pyridin-2-yl)methyl)piperidin-1-yl)ethanoltrihydrochloride

Prepared according to the method of Example 175 fromN-(4-methylthiazol-2-yl)-3-phenoxy-5-(piperidin-4-yl(pyridin-2-yl)methylthio)pyridin-2-amineand 2-hydroxyacetaldehyde. ¹H NMR (d₆-DMSO) δ 9.95 (bs, 1H), 8.50 (d,1H), 8.04 (s, 1H), 7.88 (m, 1H), 7.48-7.36 (m, 4H), 7.22 (t, 1H), 6.97(m, 3H), 6.76 (s, 1H), 4.32 (d, 1H), 3.73 (m, 2H), 3.57 (d, 1H), 3.40(d, 1H), 3.07 (m, 2H), 3.01-2.80 (m, 2H), 2.40-2.21 (m, 6H), 1.71 (m,1H), 1.57 (m, 1H), 1.42 (d, 1H).

The following compounds were made according to the method of Example175.

Example R″ Name Data 232 Me 4-methyl-N-(5-((1- ¹H NMR (d₆-DMSO) δ 10.15methylpiperidin-4- (bs, 1H), 8.47 (d, 1H), 8.02 yl)(pyridin-2- (d, 1H),7.80 (t, 1H), 7.44 (t, yl)methylthio)-3- 2H), 7.33 (m, 2H), 7.21 (t,phenoxypyridin-2- 1H), 6.96 (m, 3H), 6.72 (s, yl)thiazol-2-amine 1H),4.26 (d, 1H), 3.44 (m, trihydrochloride 1H), 3.27 (m, 1H), 2.98-2.76 (m,2H), 2.67 (d, 3H), 2.38 (d, 1H), 2.2 (s, 3H), 1.63 (m, 1H), 1.45 (m, 2H)233 iPr N-(5-((1-isopropyl- ¹H NMR (d₆-DMSO) δ 9.72 piperidin-4- (bs,1H), 8.46 (d, 1H), 8.02 yl)(pyridine-2- (d, 1H), 7.79 (t, 1H), 7.43 (t,yl)methylthio)-3- 2H), 7.32 (m, 2H), 7.21 (t, phenoxypyridin-2-yl)- 1H),6.94 (m, 3H), 6.70 (s, 4-methylthiazol-2- 1H), 4.25 (d, 1H), 3.39 (m,amine trihydrochloride 1H), 3.23 (m, 1H), 3.00-2.80 (m, 2H), 2.35 (m,2H), 2.25 (s, 3H), 1.71 (m, 1H), 1.60- 1.43 (m, 2H), 1.28 (m, 1H), 1.22(dd, 6H)

Example 2341-((6-(4-methylthiazol-2-ylamino-5-phenoxypyridin-3-ylthio)methyl)pyrrolidin-2-one

Step A: Preparation of 1-(chloromethyl)pyrrolidin-2-one: Placedpyrrolidin-2-one (2.00 g, 23.5 mmol), and paraformaldehyde (1.06 g, 35.3mmol) in chlorotrimethylsilane (60 mL) and heated to reflux for 2 hoursand then concentrated to give the title compound (2.97 g, 94.6% yield).

Step B: Preparation of1-((6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)methyl)pyrrolidin-2-one:Prepared according to the method of Example 16. ¹H NMR (d₆-DMSO) δ 10.83(bs, 1H), 8.16 (d, 1H), 7.41 (t, 2H), 7.34 (d, 1H), 7.17 (t, 1H), 7.07(d, 2H), 6.62 (s, 1H), 4.59 (s, 2H), 3.40 (t, 2H), 2.23 (s, 3H), 2.08(t, 2H), 1.84 (m, 2H).

Example 235 Ethyl2-(1-methylpiperidin-4-yl)-2-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)acetatedihydrochloride

Step A: Preparation of tert-butyl4-(2,2,2-trichloro-1-hydroxyethyl)piperidine-1-carboxylate: Placed2,2,2-trichloroacetic acid (5.746 g, 35.17 mmol) in DMF (5 mL) and addedslowly sodium 2,2,2-trichloroacetate (6.519 g, 35.17 mmol). The reactionwas stirred for 10 minutes and tert-butyl4-formylpiperidine-1-carboxylate (5.00 g, 23.44 mmol) was added. Thereaction was stirred for 40 minutes then quenched with saturated sodiumbicarbonate and filtered. The solids were washed with water and dried.The product was triturated with water and filtered to give the titlecompound (5.734 g, 73.53% yield).

Step B: Preparation of tert-butyl4-(2-ethoxy-1-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)-2-oxoethyl)piperidine-1-carboxylate:Placed methyl3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate(2.20 g, 5.48 mmol), tert-butyl4-(2,2,2-trichloro-1-hydroxyethyl)piperidine-1-carboxylate (1.86 g, 5.59mmol), and sodium ethanolate (3.55 g, 10.9 mmol) in ethanol (75 mL) andstirred at ambient temperature for 4 hours. The reaction was quenchedwith sat NH₄Cl and extracted with CH₂Cl₂. The organic phase wasconcentrated and purified by silica gel (10-25% EtOAc in hex) to givethe title compound (2.63 g, 75.5% yield).

Step C: Preparation of ethyl2-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)-2-(piperidin-4-yl)acetate:Prepared according to the method of Example 225, Step D.

Step D: Preparation of ethyl2-(1-methylpiperidin-4-yl)-2-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)acetatedihydrochloride: Prepared according to the method of Example 230. ¹H NMR(d₆-DMSO) δ 9.84 (bs, 1H), 8.18 (d, 1H), 7.44 (t, 2H), 7.30 (d, 1H),7.21 (t, 1H), 7.09 (d, 2H), 6.63 (s, 1H), 3.98 (q, 2H), 3.81 (m, 1H),3.62 (d, 1H), 3.37 (m, 2H), 2.90 (m, 2H), 2.69 (d, 3H), 2.25 (s, 3H),1.85-1.70 (m, 2H), 1.56 (m, 2H), 1.05 (t, 3H).

Example 2362-(1-methylpiperidin-4-yl)-2-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)ethanol

Placed ethyl2-(1-methylpiperidin-4-yl)-2-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)acetate(prepared in Example 235; 0.405 g, 0.812 mmol) in THF (8 mL) and cooledto 0° C. added LiAlH₄ (2.44 mL, 2.44 mmol) and warmed to ambienttemperature for minutes. Saturated NH₄Cl was slowly added and extractedwith CH₂Cl₂. The organic layer was dried, filtered, and concentrated togive the title compound (0.315 g, 84.9% yield). ¹H NMR (d₆-DMSO) δ 10.92(bs, 1H), 8.16 (d, 1H), 7.41 (t, 2H), 7.33 (d, 1H), 7.17 (t, 1H), 7.05(d, 2H), 6.60 (s, 1H), 4.82 (t, 1H), 3.49 (m, 2H), 2.87 (m, 1H), 2.80(m, 2H), 2.23 (s, 3H), 2.15 (s, 3H), 1.86-1.53 (m, 6H), 1.29 (m, 1H).

Example 237N-ethyl-2-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)-2-(piperidin-4-yl)acetamidebis(2,2,2-trifluoroacetate)

Step A: Preparation of2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)aceticacid: Prepared according to the method of Example 70, Step B, usingtert-butyl4-(2-ethoxy-1-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)-2-oxoethyl)piperidine-1-carboxylate(1.51 g, 2.59 mmol) and 4N NaOH (15 mL); (1.42 g, 98.6% yield).

Step B: Preparation of tert-butyl4-(2-(ethylamino)-1-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)-2-oxoethyl)piperidine-1-carboxylate:Prepared according to the method of Example 71, using ethylcarbonochloridate (0.0292 g, 0.269 mmol), and ethanamine; (0.034 g,21.6% yield).

Step C: Preparation ofN-ethyl-2-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)-2-(piperidin-4-yl)acetamidebis(2,2,2-trifluoroacetate): Prepared according to the method of Example225, Step D, to provide the title compound (0.040 g, 96% yield). ¹H NMR(d₆-DMSO) δ 8.53 (m, 1H), 8.20 (m, 1H), 8.17 (d, 1H), 8.02 (t, 1H), 7.42(t, 2H), 7.29 (d, 1H), 7.17 (t, 1H), 7.07 (d, 1H), 6.65 (s, 1H), 3.33(d, 1H), 3.25 (t, 2H), 2.97 (m, 2H), 2.84 (m, 2H), 2.24 (s, 3H), 2.15(d, 1H), 1.90 (m, 1H), 1.69 (d, 1H), 1.36 (m, 2H), 0.88 (t, 3H).

The following compounds were prepared according to the method of Example237, Steps B and C.

Example R″′ Name NMR Data 238

2-(6-(4-methylthiazol-2- ylamino)-5-phenoxypyridin-3-ylthio)-2-(piperidin-4-yl)-1- (pyrrolidin-1-yl)ethanonebis(2,2,2-trifluoroacetate) ¹H NMR (d₆-DMSO) δ 8.51 (m, 1H), 8.14 (m,2H), 7.43 (t, 2H), 7.20 (t, 1H), 7.15 (d, 1H), 7.10 (d, 2H), 6.65 (s,1H), 3.65 (d, 1H), 3.40 (m, 2H), 3.31 (m, 1H), 3.20 (m, 2H), 3.04 (m,1H), 2.84 (m, 2H), 2.31 (m, 1H), 2.24 (s, 3H), 1.95-1.78 (m, 2H),1.46-1.25 (m, 2H) 239

1-(indolin-1-yl)-2-(6-(4- methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)-2- (piperidin-4-yl)ethanonebis(2,2,2-trifluoroacetate) ¹H NMR (CDCl₃) δ 9.45 (bs, 1H), 9.15 (bs,1H), 8.13 (d, 1H), 8.04 (d, 1H), 7.30-7.03 (m, 9H), 6.46 (s, 1H), 4.19(m, 1H), 4.04 (m, 1H), 3.53 (m, 1H), 3.37 (d, 2H), 3.19 (m, 2H), 2.84(m, 2H), 2.63 (d, 1H), 2.43 (s, 3H), 2.02 (m, 2H), 1.70 (m, 1H), 1.55(m, 1H) 240

1-(7-azabicyclo[2.2.1]heptan- 7-yl)-2-(6-(4-methylthiazol-2- ylamino)-5-phenoxypyridin-3- ylthio)-2-(piperidin-4- yl)ethanone bis(2,2,2-trifluoroacetate) ¹H NMR (CDCl₃) δ 9.45 (bs, 1H), 9.09 (bs, 1H), 8.16(s, 1H), 7.41 (t, 2H), 7.34 (s, 1H), 7.18 (m, 3H), 6.46 (s, 1H), 4.56(m, 1H), 4.03 (m, 1H), 3.50 (m, 1H), 3.35 (m, 1H), 3.28 (d, 1H), 2.82(m, 2H), 2.52 (m, 1H), 2.43 (s, 3H), 1.95 (m, 2H), 1.68 (m, 2H),1.55-1.35 (m, 6H), 1.26 (m, 2H) 241

1-(2-methylpiperidin-1-yl)-2- (6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3- ylthio)-2-(piperidine-4- yl)ethanonebis(2,2,2- trifluoroacetate) *mixture of diastereomers ¹H NMR (CDCl₃) δ8.14 (d, 1H), 7.39 (t, 2H), 7.30 (s, 1H), 7.16 (m, 3H), 6.47 (s, 1H),4.76 (bs, 0.5H), 4.35 (m, 0.5H), 4.12 (bs, 0.5H), 3.65-3.25 (m, 3H),3.10 (m, 0.5H), 2.85 (m, 2H), 2.60 (m, 1H), 2.43 (s, 3H), 2.10-1.85 (m,2H), 1.71-1.35 (m, 6H), 1.27-0.92 (m, 6H)

Example 2422-(4-((6-(4-phenethylthiazol-2-ylamino)-5-phenoxypyridin-3-thio)(pyridin-2-yl)methyl)piperidin-1-yl)ethanol

Step A: Preparation of tert-butyl4-((6-(4-phenethylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)(pyridin-2-yl)methyl)piperidine-1-carboxylate:Prepared according to the method of Example 16 from methyl3-(6-(4-phenethylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate,potassium 2-methylpropan-2-olate, and tert-butyl4-((methylsulfonyloxy)(pyridin-2-yl)methyl)piperidine-1-carboxylate.

Step B: Preparation ofN-(4-phenethylthiazol-2-yl)-3-phenoxy-5-(piperidin-4-yl(pyridin-2-yl)methylthio)pyridin-2-amine:Prepared according to the method of Example 225, Step C.

Step C: Preparation of2-(4-((6-(4-phenethylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)(pyridin-2-yl)methyl)piperidin-1-yl)ethanol:Prepared according to the method of Example 230. ¹H NMR (d₆-DMSO) δ10.95 (bs, 1H), 9.61 (bs, 1H), 8.41 (d, 1H), 8.79 (d, 1H), 7.67 (dt,1H), 7.42 (t, 2H), 7.30-7.14 (m, 8H), 6.92 (m, 3H), 6.64 (s, 1H), 5.25(s, 1H), 4.15 (s, 1H), 3.71 (m, 2H), 3.51 (m, 2H), 3.10-2.80 (m, 8H),2.29 (m, 2H), 1.66 (m, 1H), 1.46 (m, 1H).

Example 2432-(4-((3-methyl-1,2,4-oxadiazol-5-yl)(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)methyl)piperidin-1-yl)ethanoldihydrochloride

Step A: Preparation of tert-butyl4-((3-methyl-1,2,4-oxadiazol-5-yl)(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)methyl)piperidine-1-carboxylate:Placed2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)aceticacid (0.250 g, 0.449 mmol), N-ethyl-N-isopropylpropan-2-amine (0.0638 g,0.494 mmol) in DMF (10 mL) and addedN-((dimethylamino)fluoromethylene)-N-methylmethanaminiumhexafluorophosphate(V) (0.119 g, 0.449 mmol) and stirred for 30 minutes.Added N-hydroxyacetamidine (0.0366 g, 0.494 mmol) and heated to 110° C.for 4 days. The reaction was diluted with EtOAc and washed with water,dried, filtered and concentrated. The residue was purified by reversephase chromatography to provide the title compound (0.122 g, 35.6%)Product was contaminated with ˜15% acid. Crude material was used in StepB.

Step B: Preparation of5-((3-methyl-1,2,4-oxadiazol-5-yl)(piperidin-4-yl)methylthio)-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine:Prepared according to the method of Example 225, Step D.

Step C: Preparation of provide2-(4-((3-methyl-1,2,4-oxadiazol-5-yl)(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)methyl)piperidin-1-yl)ethanoldihydrochloride: Prepared according to the method of Example 230. ¹H NMR(CDCl₃) δ 11.96 (bs, 1H), 8.02 (s, 1H), 7.44 (t, 2H), 7.25 (t, 1H), 7:09(d, 2H), 6.98 (s, 1H), 6.48 (s, 1H), 4.64 (s, 1H), 4.03 (m, 3H), 3.82(d, 1H), 3.62 (d, 1H), 3.13 (s, 2H), 2.75 (m, 2H), 2.60 (d, 1H), 2.40(s, 3H), 2.29 (s, 3H), 2.21 (m, 2H), 1.67 (m, 2H).

Example 2444-methyl-N-(3-phenoxy-5-(1-(pyridin-2-yl)ethylthio)pyridin-2-yl)thiazol-2-aminehydrochloride

4-Methyl-N-(3-phenoxy-5-(1-(pyridin-2-yl)ethylthio)pyridin-2-yl)thiazol-2-aminehydrochloride prepared in Example 33 was purified by chiralchromatography to give two enantiomers. Enantiomer 1, ¹H NMR (CDCl₃) δ8.58 (d, 1H), 8.09 (m, 1H), 8.04 (d, 1H), 7.58 (d, 2H), 7.45 (t, 2H),7.23 (t, 1H), 7.02 (d, 2H), 6.95 (d, 1H), 6.97 (s, 1H), 4.67 (q, 1H),2.28 (s, 3H), 1.62 (d, 1H). Enantiomer 2, ¹H NMR (CDCl₃) δ 8.58 (d, 1H),8.09 (m, 1H), 8.04 (d, 1H), 7.58 (d, 2H), 7.45 (t, 2H), 7.23 (t, 1H),7.02 (d, 2H), 6.95 (d, 1H), 6.97 (s, 1H), 4.67 (q, 1H), 2.28 (s, 3H),1.62 (d, 1H).

Following the method of Example 16 the following compounds were made:

Example R⁶ Name NMR Data 245

N-(5-(3-(dimethylamino)- 1-phenylpropylthio)-3- phenoxypyridin-2-yl)-4-methylthiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO) δ 10.41 (bs, 1H),8.04 (d, 1H), 7.42 (t, 2H), 7.29-7.17 (m, 6H), 6.96 (d, 1H), 6.93 (d,2H), 6.72 (s, 1H), 4.33 (t, 1H), 2.56 (m, 1H), 2.88 (m, 1H), 2.71 (d,6H), 2.28 (m, 2H), 2.25 (s, 3H). Mass spectrum (esi) m/z = 457.2 (M + H− 2HCl) 246

5-((5-cyclopropyl-1,3,4- thiadiazol-2- yl)methylthio)-N-(4-methylthiazol-2-yl)-3- phcnoxypyridin-2-amine hydrochloride ¹H NMR(d₆-DMSO) δ 8.16 (d, 1H), 7.74 (t, 2H), 7.31 (d, 1H), 7.21 (t, 1H), 7.04(d, 2H), 6.75 (s, 1H), 4.54 (s, 2H), 2.45 (m, 1H), 2.27 (s, 3H), 1.18(m, 2H), 0.94 (m, 2H); Mass spectrum (esi) m/z = 453.4 (M + H − HCl) 247

5-((1,2,4-oxadiazol-3- yi)methylthio)-N-(4- methylthiazol-2-yl)-3-phenoxypyridin-2-amine hydrochloride ¹HNMR (d₆-DMSO) δ 9.52 (s, 1H),8.16 (d, 1H), 7.45 (t, 2H), 7.32 (d, 1H), 7.22 (t, 1H), 7.07 (d, 2H),6.76 (s, 1H), 4.29 (s, 2H), 2.27 (s, 3H); Mass spectrum (esi) m/z =397.6 (M + H − HCl) 248

5-((5-methylisoxazol-3- yl)methylthio)-N-(4- methylthiazol-2-yl)-3-phenoxypyridin-2-amine hydrochloride ¹H NMR (d₆-DMSO) δ 8.15 (d, 1H),7.74 (t, 2H), 7.25 (d, 1H), 7.22 (t, 1H), 7.06 (d, 2H), 6.75 (s, 1H),6.13 (s, 1H), 4.09 (s, 2H), 2.32 (s, 3H), 2.27 (s, 3H); Mass spectrum(esi) m/z = 410.6 (M + H − HCl) 249

5-((3,5-dimethylisoxazol- 4-yl)methylthio)-N-(4- methylthiazol-2-yl)-3-phenoxypyridin-2-amine hydrochloride ¹H NMR (d₆-DMSO) δ 8.08 (d, 1H),7.43 (t, 2H), 7.24 (d, 1H), 7.22 (t, 1H), 7.03 (d, 2H), 6.76 (s, 1H),3.91 (s, 2H), 2.27 (s, 3H), 2.12 (s, 3H), 2.02 (s, 3H); Mass spectrum(esi) m/z = 424.6 (M + H − HCl) 250

5-((5-chloro-1,2,4- thiadiazol-3- yl)methylthio)-N-(4-methylthiazol-2-yl)-3- phenoxypyridin-2-amine hydrochloride ¹H NMR(d₆-DMSO) δ 8.50 (d, 1H), 7.66 (d, 1H), 7.43 (t, 2H), 7.18 (t, 1H), 7.12(d, 2H), 6.73 (s, 1H), 4.85 (s, 2H), 2.27 (s, 3H); Mass spectrum (esi)m/z = 447.6 (M + H − HCl) 251

N-(5-(isoquinolin-1- ylmethylthio)-3- phenoxypyridin-2-yl)-4-methylthiazol-2-amine dihydrochloride, ¹H NMR (d₆-DMSO) δ 8.47 (d, 1H),8.41 (d, 1H), 8.20 (m, 2H), 8.03 (m, 2H), 7.84 (t, 1H), 7.41 (t, 2H),7.19 (t, 1H), 6.92 (d, 2H), 6.89 (s, 1H), 6.74 (s, 1H), 4.93 (s, 2H),2.27 (s, 3H). 252

N-(4-((6-(4-methylthiazol- 2-ylamino)-5- phenoxypyridin-3-ylthio)methyl)thiazol-2- yl)acetamide hydrochloride ¹H NMR (d₆-DMSO) δ12.11 (s, 1H), 8.10 (d, 1H), 7.39 (t, 2H), 7.20 (t, 1H), 7.04 (d, 1H),7.01 (d, 2H), 6.72 (m, 2H), 4.06 (s, 2H), 2.26 (s, 3H), 2.12 (s, 3H).

Following the procedure in Example 16 and using methyl3-(6-(4-methylthiazol-2-ylamino)-5-(phenylthio)pyridin-3-ylthio)propanoatehydrochloride (Example 90) the following compounds were made:

Example R⁶ Name NMR Data 253

N-(5-((5-cyclopropyl-1,3,4- thiadiazol-2-yl)methylthio)-3-(phenylthio)pyridin-2-yl)-4- methylthiazol-2-amine ¹H NMR (d₆-DMSO) δ8.29 (bs, 1H), 7.44-7.31 (m, 6H), 6.57 (s, 1H), 4.49 (s, 2H), 2.46 (m,1H), 2.21 (s, 3H), 1.18 (m, 2H), 0.95 m, 2H) 254

4-methyl-N-(5-((5- methylisoxazol-3- yl)methylthio)-3-(phenylthio)pyridin-2- yl)thiazol-2-amine ¹H NMR (d₆-DMSO) δ 8.30 (s,1H), 7.73-7.31 (m, 6H), 6.63 (s, 1H), 6.12 (s, 1H), 4.09 (s, 2H), 2.33(s, 3H), 2.23 (s, 3H) 255

N-(5-((3,5-dimethylisoxazol- 4-yl)methylthio)-3-(phenylthio)pyridin-2-yl)-4- methylthiazol-2-amine ¹H NMR (d₆-DMSO) δ8.24 (s, 1H), 7.44-7.30 (m, 6H), 6.63 (s, 1H), 3.87 (s, 2H), 2.23 (s,3H), 2.09 (s, 3H), 1.96 (s, 3H)

Example 2562-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)-1-(pyrrolidin-1-yl)ethanonehydrochloride

Step A: Preparation of 2-chloro-1-(pyrrolidin-1-yl)ethanone: A solutionof mL 2-chloroacetyl chloride (1.409 mL, 17.71 mmol) and THF (50 mL) wascooled to 0° C. and pyrrolidine (1.259 g, 17.71 mmol) was slowly addedand stirred at ambient temperature for 3 hours. Partitioned betweenCH₂Cl₂ and water, and the organic layer was separated, dried, filtered,and concentrated to give the title compound (1.73 g, 66.19% yield) as aclear oil.

Step B: Preparation of2-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)-1-(pyrrolidin-1-yl)ethanonehydrochloride: Prepared according to the method of Example 16. ¹H NMR(d₆-DMSO) δ 8.21 (d, 1H), 7.45 (t, 2H), 7.39 (d, 1H), 7.23 (t, 1H), 7.13(d, 2H), 6.83 (s, 1H), 3.83 (s, 2H), 3.41 (t, 2H), 2.30 (s, 3H), 1.82(m, 2H), 1.73 (m, 2H).

Following the method of Example 32, Step A, and Example 16, thefollowing compounds were made:

Example R⁶ Name NMR Data 257

N-(2-(dimethylamino) ethyl)-N-methyl-2-(6-(4- methylthiazol-2-ylamino)-5-phenoxypyridin-3- ylthio)acetamide dihydrochloride ¹H NMR (d₆-DMSO) δ9.77 (bs, 1H), 8.19 (d, 1H), 7.42 (m, 3H), 7.19 (d, 2H), 6.69 (s, 1H),3.93 (s, 2H), 3.59 (t, 2H), 3.17 (q, 2H), 3.00 (s, 3H), 2.76 (d, 6H),2.25 (s, 3H). 258

1-(4-methylpiperazin-1- yl)-2-(6-(4-methylthiazol- 2-ylamino)-5-phenoxypyridin-3- ylthio)ethanone dihydrochloride ¹H NMR (d₆-DMSO) δ9.86 (bs, 1H), 8.21 (d, 1H), 7.42 (m, 3H), 7.16 (t, 1H), 7.06 (d, 2H),6.64 (s, 1H), 4.35 (m, 1H), 4.10 (m, 1H), 3.93 (d, 2H), 3.43 (m, 2H),3.31 (m, 1H), 3.04 (m, 1H), 2.87 (m, 2H), 2.81 (s, 3H), 2.24 (s, 3H) 259

2-(6-(4-methylthiazol-2- ylamino)-5- phenoxypyridin-3-ylthio)-N-(2-(pyrrolidin-1- yl)ethyl)acetamide dihydrochloride ¹H NMR (d₆-DMSO)δ 9.84 (bs, 1H), 8.34 (t, 1H), 8.18 (d, 1H), 7.43 (t, 2H), 7.38 (d, 1H),7.19 (t, 1H), 7.07 (d, 2H), 6.64 (s, 1H), 3.55 (s, 2H), 3.52 (m, 2H),3.34 (q, 2H), 3.13 (q, 2H), 2.94 (m, 2H), 2.23 (s, 3H), 1.96 (m, 2H),1.82 (m, 2H)

Example 260{5-[(1,1-Dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-pyridin-2-yl-methylsulfanyl]-3-phenoxy-pyridin-2-yl}-(4-methyl-thiazol-2-yl)-aminedihydrochloride

Step A: Preparation ofpyridin-2-yl(tetrahydro-2H-thiopyran-4-yl)methanol: Prepared accordingto the method of Example 225, Step A, from 2-bromopyridine andtetrahydro-2H-thiopyran-4-carbaldehyde.

Step B: Preparation of(1,1-Dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-pyridin-2-yl-methanol: Placedpyridin-2-yl(tetrahydro-2H-thiopyran-4-yl)methanol (1.560 g, 7.453 mmol)in glacial acetic acid (2 mL). Sodium perborate tetrahydrate (2.293 g,14.91 mmol) was added and stirred for 18 hours. The reaction waspartitioned between saturated sodium bisulfite and CH₂Cl₂. The solidswere filtered off, washed with water and dried to afford the titlecompound (1.233 g, 68.56% yield)

Step C: Preparation of methanesulfonic acid(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-pyridin-2-yl-methyl ester:Prepared according to the method of Example 225, Step B.

Step D: Preparation of{5-[(1,1-Dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-pyridin-2-yl-methylsulfanyl]-3-phenoxy-pyridin-2-yl}-(4-methyl-thiazol-2-yl)-aminedihydrochloride: Prepared according to the method of Example 16 usingmethyl3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate.¹H NMR (d₆-DMSO) δ 8.47 (d, 1H), 8.02 (d, 1H), 7.76 (t, 1H), 7.43 (t,2H), 7.29 (t, 2H), 7.20 (t, 1H), 7.01 (d, 1H), 6.95 (d, 2H), 6.70 (s,1H), 4.45 (d, 1H), 3.21-2.95 (m, 5H), 2.36 (m, 1H), 2.25 (s, 3H), 1.85(m, 1H), 1.74 (m, 1H), 1.61 (m, 1H).

Example 261N-(5-bromo-3-phenoxypyridin-2-yl)-4-(2-(methylthio)ethyl)thiazol-2-amine

Step A: Preparation of 1-chloro-4-(methylthio)butan-2-one: LDA preparedfrom diisopropylamine (12.44 g, 123.0 mmol) and butyl lithium (44.71 mL,111.8 mmol) combined in THF (100 mL) at −78° C. was added dropwise to asolution containing methyl 3-(methylthio)propanoate (3.00 g, 22.36mmol), and chloroiodomethane (15.77 g, 89.42 mmol) in THF (100 mL) at−78° C. over 30 minutes. The reaction was stirred for an additional 10minutes then added a solution of acetic acid 30 mL in THF (200 mL)keeping the temp below −65° C. The solution was stirred for 10 minutesand partitioned between EtOAc and brine. The organic layer was washedwith saturated bicarbonate, concentrated and purified by silica gel togive the title compound (1.021 g, 29.92% yield).

Step B: Preparation of5-bromo-N-(4-(2-(methylthio)ethyl)thiazol-2-yl)-3-phenoxypyridin-2-amine:Prepared according to the method of Example 7, Step E. ¹H NMR (d₆-DMSO)δ 10.96 (bs, 1H), 8.22 (d, 1H), 7.43 (t, 2H), 7.40 (d, 1H), 7.21 (t,1H), 7.10 (d, 2H), 6.74 (s, 1H), 2.83 (m, 2H), 2.77 (m, 2H), 2.06 (s,3H).

Example 262N-(5-bromo-3-phenoxypyridin-2-yl)-4-(2-(methylsulfonyl)ethyl)thiazol-2-amine

5-Bromo-N-(4-(2-(methylthio)ethyl)thiazol-2-yl)-3-phenoxypyridin-2-amine(1.132 g, 2.680 mmol) was dissolved in CH₂Cl₂ (25 mL) and cooled to 0°C. MCPBA (1.98 g, 8.04 mmol) was added and stirred at ambienttemperature overnight. The reaction was quenched with sodium bisulfiteand extracted with CH₂Cl₂. The organic layer was washed with saturatedsodium bicarbonate, dried, filtered, and concentrated. The residue waspurified by silica gel (15-40% EtOAc in hexanes) to provide the titlecompound (0.503 g, 41.31% yield). ¹H NMR (d₆-DMSO) δ 11.05 (bs, 1H),8.20 (d, 1H), 7.43 (t, 2H), 7.38 (m, 1H), 7.20 (t, 1H), 7.09 (d, 2H),6.79 (s, 1H), 3.43 (m, 2H), 3.00 (m, 2H), 2.97 (s, 3H).

Example 2634-methyl-N-(3-phenoxy-5-(1-(piperidin-4-yl)ethylthio)pyridin-2-yl)thiazol-2-aminebis(2,2,2-trifluoroacetate)

Step A: Preparation of tert-butyl4-(1-hydroxyethyl)piperidine-1-carboxylate: Placed tert-butyl4-formylpiperidine-1-carboxylate (2.00 g, 9.38 mmol) in THF (40 mL) andcooled to −78° C. Slowly added methylmagnesium bromide (3.44 mL, 10.3mmol) stirred for 1 hour. Slowly added saturated ammonium chloride andextracted with CH₂Cl₂. Concentrated and redisolved in 5% MeOH in CH₂Cl₂.Added ether and filtered off solids. Concentrate filtrate to give thetitle compound (1.94 g, 90.2% yield)

Step B: Preparation of tert-butyl4-(1-(methylsulfonyloxy)ethyl)piperidine-1-carboxylate: Preparedaccording to the method of Example 225, Step B.

Step C: Preparation of4-methyl-N-(3-phenoxy-5-(1-piperidin-4-yl)ethylthio)pyridin-2-yl)thiazol-2-aminebis(2,2,2-trifluoroacetate): A nitrogen purged vial was charged withmethyl3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate(0.150 g, 0.374 mmol) and THF (5 mL). Potassium 2-methylpropan-2-olate(0.934 mL, 0.934 mmol) was added and stirred at ambient temperature for30 seconds. Tert-butyl4-(1-(methylsulfonyloxy)ethyl)piperidine-1-carboxylate (0.144 g, 0.467mmol) was added and stirred at ambient temperature under nitrogen for 20hours. Saturated NH₄Cl was added and extracted with CH₂Cl₂. The organiclayer was dried, filtered, and concentrated. The residue was dissolvedin CH₂Cl₂ (5 mL) and TFA (2 mL) was added and stirred for 1 hour. Thereaction was concentrated and purified by reverse phase chromatography(with 0.1% TFA) to provide the title compound (0.0363 g, 14.8% yield).¹H NMR (d₆-DMSO) δ 8.57 (bs, 1H), 8.23 (bs, 1H), 8.18 (d, 1H), 7.42 (t,2H), 7.34 (d, 1H), 7.19 (t, 1H), 7.07 (d, 2H), 6.64 (s, 1H), 3.26 (d,2H), 3.13 (m, 1H), 2.80 (m, 2H), 2.24 (s, 3H), 1.87 (m, 2H), 1.67 (m,1H), 1.47 (m, 2H), 1.15 (d, 3H).

Example 264N-(5-(benzyloxy)-3-(phenylthio)pyridin-2-yl)-4-methylthiazol-2-aminehydrochloride

Step A: Preparation of 5-(benzyloxy)-2-chloropyridine:6-Chloropyridin-3-ol (30.00 g, 231.6 mmol), 1-(bromomethyl)benzene(43.57 g, 254.7 mmol), and potassium carbonate (80.01 g, 579.0 mmol)were added to DMF (500 mL) and stirred at ambient temperature overnight.Water was added and extracted with ether. The organic phase was washedwith 1M NaOH, dried, filtered, and concentrated to provide the titlecompound (50.8 g, 99.86% yield).

Step B: Preparation of 5-(benzyloxy)pyridin-2-amine hydrochloride: To anitrogen purged solution of mL Pd₂ (dba)₃ (10.19 g, 11.12 mmol),5-(benzyloxy)-2-chloropyridine (48.87 g, 222.5 mmol),(2-diphenyl)dicyclohexyl-phosphine (7.797 g, 22.25 mmol) and THF (700mL) was added lithium hexamethyl disilazide (267.0 mL, 267.0 mmol). Thereaction was heated at 65° C. overnight and cooled to ambienttemperature. 1M HCl (250 mL) was added and stirred for minutes.Saturated sodium bicarbonate was added slowly. The mixture was extractedseveral times with CH₂Cl₂, dried, filtered, and concentrated to give thetitle compound (52.1 g, 98.94% yield).

Step C: Preparation of 5-(benzyloxy)-3-bromopyridin-2-amine:5-(Benzyloxy)pyridin-2-amine hydrochloride (52.3 g, 221 mmol) and sodiumacetate (45.3 g, 552 mmol) were dissolved in acetic acid (300 mL).Bromine (11.3 mL, 221 mmol) was added slowly and stirred at ambienttemperature for 18 hours. After an aqueous workup, the material waspurified over silica gel to give the title compound (10.5 g, 17.0%yield).

Steps D-F: Preparation of5-(benzyloxy)-3-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine: Preparedaccording to the method of Example 7, Steps C— E.

Step F: Preparation of5-(benzyloxy)-N-(4-methylthiazol-2-yl)-3-(phenylthio)pyridin-2-amine:Prepared according to the method of Example 8 to give the title compound(2.80 g, 60.5% yield). ¹H NMR (d₆-DMSO) δ 8.22 (s, 1H), 7.57 (bs, 1H),7.49-7.30 (m, 11H), 6.68 (s, 1H), 5.18 (s, 2H), 2.25 (s, 3H).

Example 2654-methyl-N-(3-(phenylthio)-5-(2-(2-(piperidin-4-yl)ethyl)pyridin-2-yl)thiazol-2-aminebis(2,22-trifluoroacetate)

Prepared according to the method of Example 193, Steps A-C, using5-bromo-N-(4-methylthiazol-2-yl)-3-(phenylthio)thiazole-2-amine andTert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate as the startingmaterials. ¹H NMR (d₆-DMSO) δ 8.53 (bs, 1H), 8.27 (s, 1H), 8.22 (bs,1H), 7.76 (bs, 1H), 7.36 (t, 2H), 7.28 (t, 1H), 7.23 (d, 2H), 6.60 (s,1H), 3.25 (d, 2H), 2.82 (q, 2H), 2.53 (t, 2H), 2.21 (s, 3H), 1.82 (m,2H), 1.51 (m, 3H), 1.27 (m, 2H).

Example 2662,2-dimethyl-3-(2-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)propanoicacid

Step A: Preparation of methyl3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-2,2-dimethylpropanoate:Prepared according to the method of Example 7, Step E.

Step B: Preparation of methyl3-(2-(5-(3-methoxy-3-oxopropylthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-2,2-dimethylpropanoate:Prepared according to the method of Example 13.

Step C: Preparation of methyl2,2-dimethyl-3-(2-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)propanoate:Prepared according to the method of Example 127.

Step D: Preparation of2,2-dimethyl-3-(2-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)propanoicacid: Prepared according to the method of Example 45 to provide thetitle compound (0.024 g, 88% yield). ¹H NMR (CDCl₃) δ 8.44 (d, 1H), 8.29(d, 1H), 7.71 (d, 1H), 7.54 (d, 1H), 7.31-7.24 (m, 3H), 7.09 (t, 1H),7.01 (d, 2H), 6.71 (d, 1H), 6.45 (s, 1H), 2.93 (s, 2H), 1.05 (s, 6H).

Example 267 tert-butyl4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate

Step A: Preparation of 2-(2-(pyridin-3-yl)disulfanyl)pyridine: Preparedaccording to the method of Example 162, Step A from5-bromo-3-phenoxypyridin-2-amine.

Step B: Preparation of tert-butyl4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate:A solution of pyridine (0.493 mL, 6.09 mmol), (Z)-tert-butyl4-(chloro(methylsulfonyloxyimino)methyl)piperidine-1-carboxylate (0.165g, 2.03 mmol), and CH₃CN (4 mL). The reaction was heated to 40° C. for40 minutes. 3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-amine (0.400 g, 1.35mmol) was added and stirred at 50° C. over the weekend. The reaction wascooled to ambient temperature and poured into saturated aqueous NaHCO₃and extracted with EtOAc. The organic layer was dried with sodiumsulfate, filtered, and concentrated. The residue was purified on silicagel (20-25% EtOAc in hexanes) to provide the title compound (0.598 g,78.5% yield). ¹H NMR (d₆-DMSO) δ 12.33 (s, 1H), 8.39 (m, 1H), 8.37 (m,1H), 7.66 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H), 7.21-7.11 (m, 5H), 3.96(d, 2H), 2.98 (m, 3H), 1.97 (m, 2H), 1.64 (m, 2H), 1.40 (s, 9H).

Following the method of Example 267 the following compounds were made:

Example R¹³ Name NMR Data 268 iBu 3-isobutyl-N-(3-phenoxy- ¹H NMR(d₆-DMSO) δ 8.38 (m, 2H), 5-(pyridin-2- 7.67 (dt, 1H), 7.47 (d, 1H),7.42 (t, 2H), ylthio)pyridin-2-yl)-1,2,4- 7.21-7.11 (m, 5H), 2.63 (d,2H), 0.92 (d, thiadiazol-5-amine 6H) dihydrochloride 269 iPr3-isopropyl-N-(3- ¹H NMR (d₆-DMSO) δ 12.30 (bs, 1H),phenoxy-5-(pyridin-2- 8.39 (m, 2H), 7.66 (dt, 1H), 7.48 (d,ylthio)pyridin-2-yl)-1,2,4- 1H), 7.42 (t, 2H), 7.21-7.11 (m, 5H),thiadiazol-5-amine 3.08 (m, 1H), 1.29 (d, 6H) 270

N-(3-phenoxy-5-(pyridin- 2-ylthio)pyridin-2-yl)-3-(tetrahydrofuran-2-yl)- 1,2,4-thiadiazol-5-amine ¹H NMR (d₆-DMSO) δ12.30 (s, 1H), 8.40 (d, 1H), 8.37 (m, 1H), 7.66 (dt, 1H), 7.42 (t, 2H),7.42 (t, 2H), 7.21-7.11 (m, 5H), 4.06 (t, 1H), 3.90-3.75 (m, 3H), 3.60(m, 1H), 2.27 (q, 2H).

Example 271N-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(piperidin-4-yl)-1,2,4-thiadiazol-5-aminetrihydrochloride

Tert-butyl4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate(0.587 g, 1.04 mmol) was dissolved in 1:1 CH₂Cl₂/methanol and 4N HCl indioxane added. The reaction was stirred at ambient temperature for 1hour. The reaction was concentrated and dried in a vacuum oven toprovide the title compound (0.473 g, 98.0% yield). ¹H NMR (d₆-DMSO) δ12.39 (s, 1H), 8.95 (bs, 1H), 8.80 (bs, 1H), 8.39 (d, 1H), 8.37 (m, 1H),7.67 (dt, 1H), 7.47 (d, 1H), 7.43 (t, 2H), 7.22-7.12 (m, 5H), 3.30 (d,2H), 3.16-2.99 (m, 3H), 2.17 (d, 2H), 1.98 (m, 2H).

Example 2721-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone

3-Phenoxy-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(pyridin-2-ylthio)pyridin-2-amine (0.075 g, 0.16 mmol), TEA (0.090 mL, 0.65 mmol), andacetic anhydride (0.017 g, 0.16 mmol) were added to THF and stirred for3 hr. Water was added and extracted with CH₂Cl₂. The organic layer wasdried, filtered, and concentrated. The residue was purified by silicagel (5% MeOH in CH₂Cl₂) to provide the title compound (0.044 g, 54%yield). ¹H NMR (d₆-DMSO) δ 12.34 (s, 1H), 8.38 (m, 2H), 7.67 (dt, 1H),7.48 (d, 1H), 7.42 (t, 2H), 7.21-7.11 (m, 5H), 4.32 (d, 1H), 3.84 (d,1H), 3.19 (m, 1H), 3.05 (m, 1H), 2.76 (t, 1H), 2.01 (m, 5H), 1.74 (m,1H), 1.59 (m, 1H).

The following compounds were made according to the method of Example272.

Example R^(a) Name NMR Data 273

2-methoxy-1-(4-(5-(3- phenoxy-5-(piperidi-2- ylthio)piperidi-2-ylamino)-1,2,4- thiadiazol-3- yl)piperidine-1- yl)ethanonedihydrochloride ¹H NMR (d₆-DMSO) δ 12.34 (s, 1H), 8.39 (d, 1H), 8.37 (m,1H), 7.67 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H), 7.21- 7.11 (m, 5H), 4.30(d, 1H), 4.09 (q, 2H), 3.81 (d, 1H), 3.28 (s, 3H), 3.18-3.03 (m, 2H),2.81 (m, 1H), 2.01 (d, 2H), 1.73 (m, 1H), 1.63 (m, 1H). 274

2-(dimethylamino)-1-(4- (5-(3-phenoxy-5- (pyridin-2- ylthio)pyridin-2-ylamino)-1,2,4- thiadiazol-3- yl)piperidin-1- yl)ethanonedihydrochloride ¹H NMR (d₆-DMSO) δ 12.34 (s, 1H), 9.54 (bs, 1H), 8.39(d, 1H), 8.37 (m, 1H), 7.67 (dt, 1H), 7.48 (d, 1H), 7.43 (t, 2H),7.21-7.11 (m, 5H), 4.32 (m, 3H), 3.65 (d, 1H), 3.23 (m, 1H), 3.14 (m,1H), 2.96 (t, 1H), 2.81 (d, 6H), 2.08 (d, 2H), 1.85-1.60 (m, 2H). 275

N,N-dimethyl-4-(5-(3- phenoxy-5-(pyridin-2- ylthio)pyridin-2-ylamino)-1,2,4- thiadiazol-3- yl)piperidine-1- carboxamidedihydrochloride ¹H NMR (d₆-DMSO) δ 12.34 (s, 1H), 8.39 (d, 1H), 8.37 (m,1H), 7.66 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H), 7.21- 7.11 (m, 5H), 3.58(d, 2H), 2.96 (m, 1H), 2.84 (t, 2H), 2.73 (s, 6H), 1.96 (m, 2H), 1.74(m, 2H). 276

N,N-dimethyl-4-(5-(3- phenoxy-5-(pyridin-2- ylthio)pyridin-2-ylamino)-1,2,4- thiadiazol-3- yl)piperidine-1- sulfonamidedihydrochloride ¹H NMR (d₆-DMSO) δ 12.36 (s, 1H), 8.39 (d, 1H), 8.37 (m,1H), 7.67 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H), 7.21- 7.11 (m, 5H), 3.60(d, 2H), 2.99 (m, 3H), 2.75 (s, 6H), 2.06 (m, 2H), 1.77 (m, 2H). 277

2-methyl-1-(4-(5-(3- phenoxy-5-(pyridin-2- ylthio)pyridin-2-ylamino)-1,2,4- thiadiazol-3- yl)piperidin-1- yl)propan-1-onedihydrochloride ¹H NMR (d₆-DMSO) δ 12.34 (s, 1H), 8.39 (d, 1H), 8.37 (m,1H), 7.66 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H), 7.21- 7.11 (m, 5H), 4.37(d, 1H), 3.98 (d, 1H), 3.20 (t, 1H), 3.07 (m, 1H), 2.89 (m, 1H), 2.75(t, 1H), 2.02 (m, 2H), 1.70 (m, 1H), 1.57 (m, 1H), 1.00 (d, 6H). 278

3-(1-(methylsulfonyl) piperidin-4-yl)-N- (3-phenoxy-5- (pyridin-2-ylthio)pyridin-2-yl)- 1,2,4-thiadiazol-5-amine dihydrochloride ¹H NMR(d₆-DMSO) δ 12.36 (s, 1H), 8.40 (d, 1H), 8.37 (m, 1H), 7.67 (dt, 1H),7.48 (d, 1H), 7.43 (t, 2H), 7.21- 7.11 (m, 5H), 3.59 (d, 2H), 2.95-2.86(m, 6H), 2.14 (d, 2H), 1.81 (m, 2H). 279

2-oxo-2-(4-(5-(3- phenoxy-5-(pyridin-2- ylthio)pyridin-2-ylamino)-1,2,4- thiadiazol-3- yl)piperidin-1-yl)ethyl acetatedihydrochloride ¹H NMR (d₆-DMSO) δ 12.36 (s, 1H), 8.39 (d, 1H), 8.37 (m,1H), 7.66 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H), 7.21- 7.11 (m, 5H), 4.79(m, 2H), 4.26 (d, 1H), 3.75 (d, 1H), 3.22-3.04 (m, 2H), 2.83 (t, 1H),2.07 (s, 3H), 1.76 (m, 1H), 1.61 (m, 1H).

Example 2804-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxamidedihydrochloride

To a solution of3-phenoxy-N-(3-(piperidine-4-yl)-1,2,4-thiadiazol-5-yl)-5-(piperidi-2-ylthio)piperidi-2-amine(0.055 g, 0.119 mmol) in CH₂Cl₂ (4 mL) was added pyridine (0.0940 g,1.19 mmol), acetic acid (0.0714 g, 1.19 mmol), TEA (0.033 mL, 0.238mmol), and potassium cyanate (0.0193 g, 0.238 mmol). The reaction wasstirred for 18 hours. Water was added and extracted with CH₂Cl₂. Theorganic layer was dried, filtered, and concentrated. The residue waspurified by silica gel (1-4% MeOH in CH₂Cl₂) to give the title compound(0.0333 g, 48.4% yield) after HCl salt formation. ¹H NMR (d₆-DMSO) δ12.33 (s, 1H), 8.39 (d, 1H), 8.37 (m, 1H), 7.67 (dt, 1H), 7.47 (d, 1H),7.42 (t, 2H), 7.21-7.11 (m, 51H), 3.94 (d, 2H), 2.97 (m, 1H), 2.83 (t,2H), 1.19 (m, 2H), 1.64 (m, 2H).

Example 2812-hydroxy-1-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone

2-Oxo-2-(4-(5-(3-phenoxy-5-(piperidi-2-ylthio)piperidi-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-yl)ethylacetate (0.089 g, 0.158 mmol) and potassium carbonate (0.109 g, 0.791mmol) were refluxed in ethanol (25 mL) for 2 hours. The reaction wascooled to ambient temperature, filtered and concentrated. The residuewas purified by silica gel (1-2% MeOH in EtOAc) to give the titlecompound (0.030 g, 36.4% yield). ¹H NMR (d₆-DMSO) δ 12.34 (s, 1H), 8.39(d, 1H), 8.37 (m, 1H), 7.66 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H),7.21-7.11 (m, 5H), 4.49 (t, 1H), 4.31 (d, 1H), 4.10 (t, 2H), 3.71 (d,1H), 3.10 (m, 2H), 2.86 (t, 1H), 2.02 (m, 2H), 1.79-1.60 (m, 2H).

Example 282 tert-Butyl2-oxo-2-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethylcarbamate

3-Phenoxy-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(pyridin-2-ylthio)pyridin-2-amine(0.100 g, 0.2162 mmol), 2-(tert-butoxycarbonyl)acetic acid (0.04544 g,0.2594 mmol),N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (0.06216 g, 0.3243 mmol), and N,N-dimethylpyridin-4-amine(0.002641 g, 0.02162 mmol) were dissolved in CH₂Cl₂ (5 mL).Triethylamine (0.04375 g, 0.4323 mmol) was added and the solution wasstirred at ambient temperature for 3 hours. Water was added and thesolution was extracted with CH₂Cl₂, dried, filtered, and concentrated.The residue was purified by silica gel (1-2% MeOH in CH₂Cl₂) to give thetitle compound (0.1116 g, 83.30% yield). ¹H NMR (d₆-DMSO) δ 12.35 (s,1H), 8.39 (d, 1H), 8.37 (m, 1H), 7.66 (dt, 1H), 7.47 (d, 1H), 7.42 (t,2H), 7.21-7.11 (m, 5H), 6.73 (t, 1H), 4.29 (t, 1H), 3.81 (m, 3H),3.20-3.02 (m, 2H), 2.81 (t, 1H), 2.01 (m, 2H), 1.76-1.53 (m, 2H), 1.38(s, 9H).

Example 283(R)-2-hydroxy-1-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)propan-1-one

3-Phenoxy-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(pyridin-2-ylthio)pyridin-2-amine(Example 39, step C, 0.075 g, 0.16 mmol), (S)-2-hydroxypropanoic acid(0.018 g, 0.19 mmol),N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (0.047 g, 0.24 mmol), and N,N-dimethylpyridin-4-amine(0.002 g, 0.016 mmol) were dissolved in CH₂Cl₂ (5 mL). Triethylamine(0.033 g, 0.32 mmol) was added and the solution was stirred at roomtemperature for 3 hours. Water was added and extracted with CH₂Cl₂,dried, filtered, and concentrated. The residue was purified by silicagel (1-2% MeOH in CH₂Cl₂) to give(R)-2-hydroxy-1-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)propan-1-one(0.023 g, 27% yield). ¹H NMR (d₆-DMSO) δ 12.34 (s, 1H), 8.39 (d, 1H),8.37 (m, 1H), 7.66 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H), 7.21-7.11 (m,5H), 4.82 (t, 1H), 4.45 (m, 1H), 4.34 (m, 1H), 4.01 (m, 1H), 3.25-3.04(m, 2H), 2.84 (m, 1H), 2.02 (d, 2H), 1.81-1.55 (m, 2H), 1.18 (d, 3H).

The following compound was made according to the method of Example 282:

Example R^(a) Name NMR Data 283

2-methyl-1-(4-(5-(3- phenoxy-5-(pyridin-2- ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3- yl)piperidin-1-yl)propan-1- one ¹H NMR (d₆-DMSO) δ12.34 (s, 1H), 8.39 (d, 1H), 8.37 (m, 1H), 7.66 (dt, 1H), 7.47 (d, 1H),7.42 (t, 2H), 7.21-7.11 (m, 5H), 4.82 (t, 1H), 4.45 (m, 1H), 4.34 (m,1H), 4.01 (m, 1H), 3.25-3.04 (m, 2H), 2.84 (m, 1H), 2.02 (d, 2H),1.81-1.55 (m, 2H), 1.18 (d, 3H).

Example 285

2-amino-1-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanonedihydrochloride

tert-Butyl2-oxo-2-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethylcarbamate(0.098 g, 0.16 mmol) was dissolved in CH₂Cl₂:MeOH (1:1, 20 mL) and added5 mL of 4M HCl in dioxane and stirred for 2 hours. The reaction wasconcentrated and dried in high vacuum oven to provide2-amino-1-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanonedihydrochloride (0.081 g, 78% yield). ¹H NMR (d₆-DMSO) δ 12.34 (s, 1H),8.39 (d, 1H), 8.37 (m, 1H), 8.13 (m, 3H), 7.67 (dt, 1H), 7.48 (d, 1H),7.43 (t, 2H), 7.21-7.11 (m, 5H), 4.32 (d, 1H), 3.90 (m, 2H), 3.70 (m,2H), 3.48 (m, 1H), 3.26-3.02 (m, 2H), 2.94 (t, 1H), 2.06 (d, 2H),1.76-1.53 (m, 2H).

Example 2862-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanolbis(2,2,2-trifluoroacetate)

Prepared according to the method of Example 230 from3-phenoxy-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(pyridin-2-ylthio)pyridin-2-amine.¹H NMR (d₆-DMSO) δ 12.37 (s, 1H), 9.26 (bs, 1H), 8.39 (d, 1H), 8.37 (d,1H), 7.67 (dt, 1H), 7.48 (d, 1H), 7.43 (t, 2H), 7.22-7.12 (m, 5H), 3.96(s, 1H), 3.77 (t, 2H), 3.61 (d, 2H), 3.20-3.06 (m, 5H), 2.26 (d, 2H),2.00 (m, 2H).

Example 2874-(5-(3-Phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-sulfonamidebis(2,2,2-trifluoroacetate)

N-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(piperidin-4-yl)-1,2,4-thiadiazol-5-amine(Example 34, step C, 7.2 g, 14.01 mmol) and sulfamide (1.414 g, 14.71mmol) were dissolved in dioxane (15 mL) and heated to reflux overnight.The reaction was cooled and water was added and extracted with DCM. Theorganic layer was dried over sodium sulfate, filtered and concentrated.The residue was purified by silica gel (1:1 EtOAc in DCM). The purifiedmaterial was dissolved in DCM and 2M HCl in ether was added. Thesolution was concentrated and dried in a vacuum oven to afford4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-sulfonamidehydrochloride (3.145 g, 38.8% yield). ¹H NMR (d₆-DMSO) δ 12.35 (s, 1H),8.39 (d, 1H), 8.37 (m, 1H), 7.67 (dt, 1H), 7.48 (d, 1H), 7.42 (t, 2H),7.21-7.11 (m, 5H), 6.73 (bs, 2H), 3.47 (d, 2H), 2.87 (m, 1H), 2.71 (t,2H), 2.11 (d, 2H), 1.85 (m, 2H).

Example 2883-(1-(2-aminoethylsulfonyl)piperidin-4-yl)-N-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-yl)-1,2,4-thiadiazol-5-amine

Step A: Preparation of2-(2-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-ylsulfonyl)ethyl)isoindoline-1,3-dione:Prepared according to the method of Example 272 from3-phenoxy-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(pyridin-2-ylthio)pyridin-2-amine.

Step B: Preparation ofN-(3-(1-(2-aminoethylsulfonyl)piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-amine:2-(2-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1:ylsulfonyl)ethyl)isoindoline-1,3-dione (0.110 g, 0.157 mmol) andhydrazine monohydrate (0.0236 g, 0.472 mmol) were dissolved in EtOH (25mL) and heated to reflux for 8 hours. The reaction was cooled to ambienttemperature and the solids filtered and triturated with EtOH to affordthe title compound (0.013 g, 14.5% yield). ¹H NMR (d₆-DMSO) δ 8.38 (d,1H), 8.36 (m, 1H), 7.66 (dt, 1H), 7.45 (d, 1H), 7.41 (t, 2H), 7.20-7.10(m, 5H), 3.61 (d, 2H), 3.12 (t, 2H), 3.01-2.89 (m, 5H), 2.09 (d, 2H),1.79 (m, 2H).

Example 289 tert-butyl3-methyl-4-(2-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate

Step A: Preparation of tert-butyl4-(methoxy(methyl)carbamoyl)-3-methylpiperidine-1-carboxylate: To asolution of 1-(tert-butoxycarbonyl)-3-methylpiperidine-4-carboxylic acid(3.00 g, 12.3 mmol) in CH₂Cl₂ (200 mL) was addeddi(1H-imidazol-1-yl)methanone (2.19 g, 13.6 mmol) portionwise. After thebubbling ceased (˜60 minutes), N-methoxymethanamine hydrochloride (1.32g, 13.6 mmol) was added in one portion. The mixture was allowed to stirovernight at ambient temperature, then was washed with water, 1N HCl,and saturated sodium bicarbonate. The organic layer was dried, filtered,and concentrated to give the desired product (2.29 g, 64.8% yield) as acolorless oil.

Step B: Preparation of tert-butyl4-acetyl-3-methylpiperidine-1-carboxylate: 3.0 M methylmagnesiumchloride in THF (4.50 mL, 13.5 mmol) was added dropwise to a solution oftert-butyl 4-(methoxy(methyl)carbamoyl)-3-methylpiperidine-1-carboxylate(3.10 g, 10.8 mmol) in THF (50 mL) at 0° C. The reaction was warmed toambient temperature and stirred for 90 minutes. The reaction waspartitioned between ether and 2N HCl, washed the organic layer twicewith water, brine, dried, and concentrated to afford the title compound(2.32 g, 84.3% yield) as clear oil.

Step C: Preparation of tert-butyl4-(2-bromoacetyl)-3-methylpiperidine-1-carboxylate: To a cooled (−78°C.) solution of LDA (5.69 mL, 11.4 mmol) in THF (100 mL) was addeddropwise over 40 minutes a solution of tert-butyl4-acetyl-3-methylpiperidine-1-carboxylate (2.29 g, 9.48 mmol) in THF (40mL). After an additional 25 minutes, chlorotrimethylsilane (2.41 mL,18.9 mmol) was added dropwise over 20 minutes. After stirring for 1 hourthe reaction was poured into 600 mL saturated sodium bicarbonate andextracted with ether (2×400 mL). The combined ether layers were washedwith brine, dried, filtered, and concentrated to afford crude TMS-enolether, which was then redissolved in 500 mL THF and cooled to 0° C. andtreated with sodium bicarbonate (1.20 g, 14.2 mmol), followed by NBS(1.69 g, 9.48 mmol). The reaction was allowed to warm to ambienttemperature while stirring for 90 minutes at which point it was pouredinto 400 mL of saturated sodium bicarbonate solution and extracted withEt₂O and the combined organic layers were washed with saturated NaHCO₃,brine, dried, and concentrated to give the title compound (3.35 g, 110%yield) as an orange oil.

Step D: Preparation of tert-butyl3-methyl-4-(2-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate:Prepared according to the method of Example 7, Step E; (0.302 g, 68.6%yield). ¹H NMR (d₆-DMSO) δ 11.06 (s, 1H), 8.37 (m, 1H), 8.26 (d, 1H),7.65 (dt, 1H), 7.41 (t, 2H), 7.32 (d, 1H), 7.20-7.11 (m, 4H), 7.06 (d,1H), 6.67 (s, 1H), 4.10 (m, 1H), 3.85 (m, 1H), 3.01-2.72 (m, 3H), 2.26(m, 1H), 1.84-1.65 (m, 2H), 1.40 (s, 9H), 0.59 (d, 3H).

Example 2901-(3-methyl-4-(2-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanonedihydrochloride

Step A: Preparation ofN-(4-(3-methylpiperidin-4-yl)thiazol-2-yl)-3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-amine:Prepared according to the method of Example 271 from tert-butyl3-methyl-4-(2-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine1-carboxylate.

Step B: Preparation of1-(3-methyl-4-(2-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanonedihydrochloride: Prepared according to the method of Example 272 toprovide the title compound (0.0553 g, 51.4% yield) as a 1:1 mixture ofdiastereomers. ¹H NMR (d₆-DMSO) δ 8.37 (d, 1H), 8.29 (s, 1H), 7.67 (dt,1H), 7.43 (t, 2H), 7.37 (d, 1H), 7.17 (m, 4H), 7.10 (d, 1H), 6.73 (d,1H), 4.50 (d, 0.5H), 4.27 (d, 0.5H), 3.94 (d, 0.5H), 3.74 (d, 0.5H),3.33 (d, 0.5H), 3.15 (t, 0.5), 3.04 (m, 1H), 2.87 (d, 0.5), 2.67 (m,0.5H), 2.32 (m, 1H), 2.05 (s, 1.5H), 1.98 (s, 1.5H), 1.89-1.69 (m, 2H),0.64 (d, 1.5H), 0.56 (d, 1.5H).

Example 2911-(4-(2-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanonedihydrochloride

Step A: Preparation of1-benzoyl-3-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-yl)thiourea:Prepared according to the method of Example 7, Step C, from3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-amine.

Step B: Preparation of1-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-yl)thiourea: Preparedaccording to the method of Example 39, Step D.

Step C: Preparation of1-(4-(2-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanonedihydrochloride: Prepared according to the method of Example 7, Step Ein 6.2% yield after HCl salt formation. ¹H NMR (d₆-DMSO) δ 8.38 (m, 1H),8.29 (d, 1H), 7.67 (dt, 1H), 7.45-7.37 (m, 3H), 7.21-7.08 (m, 5H), 6.78(s, 1H), 4.32 (d, 1H), 3.87 (d, 1H), 3.13 (t, 1H), 2.87 (m, 1H), 2.64(t, 1H), 2.01 (s, 3H), 1.95 (m, 2H), 1.63-1.39 (m, 2H).

Example 292N-(5-Bromo-3-phenoxypyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine

Heated a mixture of 2-chloro-3-isothiocyanatopyridine (0.257 g, 1.51mmol) and 5-bromo-3-phenoxypyridin-2-amine (0.400 g, 1.51 mmol) in DMF(4 mL) at 80° C. for 3 hours. Heated at 120° C. overnight. Cooled,partitioned between 2N NaOH and ethyl acetate. Washed the organic layertwice with water, brine, dried, and concentrated. Subjected the residueto Biotage, eluting with 3:1 hexane:ethyl acetate to afford the titlecompound (0.465 g, 77.2% yield) as a white powder. ¹H NMR (d₆-DMSO) δ7.15 (d, 2H), 7.23 (t, 1H), 7.40-7.50 (m, 4H), 7.92 (s, 1H), 8.34 (s,1H), 8.37 (d, 1H), 11.63 (bs, 1H).

Example 293 Methyl3-(5-phenoxy-6-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)propanoate

Prepared according to the method of Example 13 fromN-(5-bromo-3-phenoxypyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine, methyl3-mercaptopropanoate and N-ethyl-N-isopropylpropan-2-amine in 75% yield.¹H NMR (d₆-DMSO) δ 2.59 (t, 2H), 3.09 (t, 2H), 3.56 (s, 3H), 7.12 (d,2H), 7.20 (t, 1H), 7.38-7.46 (m, 4H), 7.91 (bs, 1H), 8.24 (s, 1H), 8.36(d, 1H), 11.53 (bs, 1H).

Example 294N-(3-Phenoxy-5-(pyridin-4-ylthio)pyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine

Prepared according to the method of Example 292 from2-chloro-3-isothiocyanatopyridine (0.116 g, 0.677 mmol) and3-phenoxy-5-(pyridin-4-ylthio)pyridin-2-amine. ¹H NMR (d₆-DMSO)S 7.10(d, 2H), 7.17-7.23 (m, 3H), 7.40-7.47 (m, 4H), 7.97 (bs, 1H), 8.36-8.41(m, 4H), 11.88 (bs, 1H).

Example 295 Preparation of4-(2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)benzonitrile

Step A: Preparation ofN-(3-bromopyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine: Heated a mixtureof 2-chloro-3-isothiocyanatopyridine (0.986 g, 5.78 mmol) and3-bromopyridin-2-amine (1.00 g, 5.78 mmol) in DMF (4 mL) at 80° C. for 3hours. Heated at 120° C. overnight. Cooled, partitioned between ethylacetate and water, washed with 2N NaOH, water, brine, dried, andconcentrated. Crystallized from dichloromethane:hexanes (1:10, 110 mL)and filtered. The filtered material was further purified by dissolvingin dichloromethane (10 mL), and subjecting to MPLC (Biotage) elutingwith 3:2 hexane:ethyl acetate. The higher Rf component was concentratedto afford the title compound (0.654 g, 36.8% yield) as a white powder.

Step B: Preparation of methyl3-(2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)propanoate: Amixture of N-(3-bromopyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine (0.55g, 1.79 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene(0.052 g, 0.090 mmol), Pd₂dba₃ (0.041 g, 0.045 mmol), methyl3-mercaptopropanoate (0.21 mL, 1.88 mmol),N-ethyl-N-isopropylpropan-2-amine (0.62 mL, 3.60 mmol), and dioxane (40mL) was heated to 95° C. under nitrogen. Cooled to ambient temperatureand filtered the solids. Concentrated and purified by MPLC (Biotage)eluting with 1:1 hexane:ethyl acetate to afford the title compound(0.541 g, 87% yield) as a dark yellow oil.

Step C: Preparation of4-(2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)benzonitrile:Added potassium 2-methylpropan-2-olate (0.097 g, 0.87 mmol) to asolution of methyl3-(2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)propanoate (100mg, 0.289 mmol) in DMSO (1 mL). Stirred 15 minutes, added4-fluorobenzonitrile (0.105 g, 0.866 mmol) and stirred overnight.Partitioned between ethyl acetate and water. Washed the organic layerwith water, brine, dried, and concentrated. Purified by MPLC elutingwith 3:2 hexane:ethyl acetate to afford the title compound (0.034 g, 33%yield) as a white powder: ¹H NMR (CDCl₃). 7.10-7.15 (m, 3H), 7.32 (dd,1H), 7.52 (d, 2H), 7.87 (d, 1H), 7.96 (d, 1H), 8.42 (d, 1H), 8.58 (d,1H), 9.10 (bs, 1H).

Example 2962-(2-(Thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)benzonitrile

Prepared according to the method of Example 295, step C. ¹H NMR (CDCl₃)δ 6.91 (d, 1H), 7.11 (dd, 1H), 7.27-7.34 (m, 2H), 7.42 (t, 1H), 7.69 (d,1H), 7.90 (d, 1H), 7.99 (d, 1H), 8.43 (d, 1H), 8.57 (d, 1H), 9.13 (bs,1H).

Example 2974-(5-Phenoxy-6-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)benzonitrile

Prepared according to the method of Example 295, step C. ¹H NMR (CDCl₃)δ 7.07-7.16 (m, 4H), 7.25 (m, 1H), 7.35 (dd, 1H), 7.41-7.46 (m, 2H),7.49 (d, 2H), 7.93 (d, 1H), 8.30 (s, 1H), 8.44 (d, 1H), 9.00 (bs, 1H).

Example 298N-(3-Phenoxy-5-(pyrimidin-2-ylthio)pyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine

Prepared according to the method of Example 295, step C. ¹H NMR (CDCl₃)δ 7.00 (t, 1H), 7.13 (d, 2H), 7.23 (t, 1H), 7.31-7.43 (m, 4H), 7.91 (d,1H), 8.35 (s, 1H), 8.42 (d, 1H), 8.47 (d, 2H), 9.02 (bs, 1H).

Example 299N-(3-Phenoxy-5-(thieno[3,2-b]pyridin-7-thio)pyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine

Prepared according to the method of Example 295, step C. ¹H NMR (CDCl₃)δ 6.79 (d, 1H), 7.06 (d, 2H), 7.24 (m, 2H), 7.33-7.42 (m, 3H), 7.55 (d,1H), 7.74 (d, 1H), 7.93 (d, 1H), 8.38 (s, 1H), 8.44 (d, 1H), 8.49 (d,1H), 9.07 (bs, 1H).

Example 300N-(3-(Thieno[3,2-b]pyridin-7-ylthio)pyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine

Prepared according to the method of Example 295, step C. ¹H NMR (CDCl₃)δ 6.64 (d, 1H), 7.13 (dd, 1H), 7.31 (dd, 1H), 7.59 (d, 1H), 7.80 (d,1H), 7.85 (d, 1H), 8.01 (d, 1H), 8.42 (d, 1H), 8.47 (d, 1H), 8.61 (d,1H), 9.16 (bs, 1H).

Example 301 Preparation ofN-(5-bromo-3-phenoxypyrazin-2-thiazin-2-yl)thiazolo[5,4-b]pyridin-2-amine

Step A: Preparation of 5-bromo-3-phenoxypyrazin-2-amine: Added sodiumhydride (0.348 g, 8.70 mmol) to a solution of phenol (0.819 g, 8.70mmol) in THF (50 mL) at 0° C. and stirred 30 minutes. Added3,5-dibromopyrazin-2-amine (2.00 g, 7.91 mmol) in THF (10 mL). Removedthe ice bath and refluxed overnight. Partitioned between ethyl acetateand water, washed with brine, dried, and concentrated. Purified by MPLC(Biotage) eluting with 5:1 hexane:ethyl acetate to afford the titlecompound (1.36 g, 64.6% yield) as a light yellow solid.

Step B: Preparation ofN-(5-bromo-3-phenoxypyrazin-2-yl)thiazolo[5,4-b]pyridin-2-amine:5-Bromo-3-phenoxypyrazin-2-amine (0.100 g, 0.376 mmol) and2-chloro-3-isothiocyanatopyridine (0.0641 g, 0.376 mmol) afforded thetitle compound (0.078 g, 51.9% yield) as light yellow crystals: ¹H NMR(d₆-DMSO) δ 7.28-7.33 (m, 3H), 7.43-7.51 (m, 3H), 7.94 (d, 1H), 8.27 (s,1H), 8.39 (d, 1H), 12.30 (bs, 1H).

Example 302N-(5-Bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine

Prepared according to the method of Example 301, step B. ¹H NMR (CDCl₃)δ 7.08-7.18 (m, 5H), 7.34 (dd, 1H), 7.91 (d, 1H), 8.21 (s, 1H), 8.43 (d,1H), 8.83 (bs, 1H).

Example 303 Preparation of4-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-yloxy)benzonitrile

Step A: Preparation of 4-(2-aminopyridin-3-yloxy)benzonitrile: Heated amixture of potassium carbonate (31.38 g, 227.0 mmol),2-aminopyridin-3-ol (10.00 g, 90.82 mmol), 4-fluorobenzonitrile (11.00g, 90.82 mmol), and DMF (80 mL) at 90° C. for 3 hours. Cooled,partitioned between ethyl acetate and water, washed the organic layertwice with water, once with 2N NaOH, brine, dried, and concentrated.Dissolved the residue in dichloromethane (20 mL), added hexanes (150mL), concentrated to 130 mL, filtered, and dried to afford the titlecompound (13.95 g, 72.72% yield) as a tan powder.

Step B: Preparation of 4-(2-amino-5-bromopyridin-3-yloxy)benzonitrile:Placed 4-(2-aminopyridin-3-yloxy)benzonitrile (13.95 g, 66.05 mmol) inacetic acid (50 mL) and cooled to 0° C. Slowly added bromine (4.229 mL,82.56 mmol) and stirred for an hour. The reaction mixture was pouredonto saturated sodium bisulfite and ice. Extracted with dichloromethanethree times, washed with 2N NaOH, water, brine, dried, and concentrated.Purified by MPLC eluting with 3:2 hexane:ethyl acetate to afford thetitle compound (12.7 g, 66.28% yield) as a light yellow solid.

Step C: Preparation of4-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-yloxy)benzonitrile:Prepared according to the method of Example 301, Step B. ¹H NMR(d₆-DMSO) δ 7.21 (d, 2H), 7.41 (dd, 1H), 7.85-7.88 (m, 3H), 7.94 (s,1H), 8.36 (d, 1H), 8.47 (s, 1H), 11.91 (bs, 1H).

Example 304 Preparation of4-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)benzonitrile

Step A: Preparation of1-benzoyl-3-(5-bromo-3-(4-cyanophenoxy)pyridin-2-yl)thiourea: Preparedaccording to the method of Example 7, step C from benzoyl isothiocyanateand 4-(2-amino-5-bromopyridin-3-yloxy)benzonitrile.

Step B: Preparation of1-(5-bromo-3-(4-cyanophenoxy)pyridin-2-yl)thiourea: Added 3 M aqueoussodium hydroxide (4.41 mL, 13.2 mmol) to a mixture of1-benzoyl-3-(5-bromo-3-(4-cyanophenoxy)pyridin-2-yl)thiourea (3.00 g,6.62 mmol) and MeOH (50 mL) and heated to 50° C. for 2 hours. Cooled,partitioned between ethyl acetate and water, washed twice with water,brine, dried, and concentrated. Added ethyl acetate (6 mL), heated totry to afford a solution. Added hexanes (8 mL) slowly, and cooled andtriturated for 15 minutes. Filtered, to afford the title compound a(1.70 g, 73.6% yield) as a white solid.

Step C: Preparation of4-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)benzonitrile:Prepared according to the method of Example 7, step E. ¹H NMR (d₆-DMSO)δ 2.20 (s, 3H), 6.57 (s, 1H), 7.13 (d, 2H), 7.82 (s, 1H), 7.84 (d, 2H),8.34 (s, 1H), 11.20 (bs, 1H).

Example 305 Preparation of methyl4-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)benzoatehydrochloride

Step A: Preparation of methyl 4-(2-nitropyridin-3-ylthio)benzoate:Stirred a mixture of methyl 4-mercaptobenzoate (4.46 g, 26.5 mmol),3-chloro-2-nitropyridine (4.00 g, 25.2 mmol) and cesium carbonate (9.04g, 27.8 mmol) in DMSO (60 mL) at ambient temperature for 90 minutes. Thesolution was diluted with water, extracted with EtOAc, dried, andconcentrated. The crude solid was suspended in MeOH (80 mL) andtriturated for 0.5 hours. The solid was filtered and dried to providethe title compound (6.16 g, 84.1% yield).

Step B: Preparation of methyl 4-(2-aminopyridin-3-ylthio)benzoate: Addedzinc powder (13.88 g, 212.2 mmol) slowly to a solution of methyl4-(2-nitropyridin-3-ylthio)benzoate (6.16 g, 21.22 mmol) in acetic acid(75 mL) at ambient temperature in an ambient water bath. Stirred for anhour, diluted with dichloromethane, and filtered through celite. Washedthe celite pad several times with dichloromethane. Concentrated thefiltrate, and partitioned the residue between 2N NaOH and ethyl acetate.The organic layer was washed with water, brine, dried and concentratedto afford the title compound (5.5 g, 99.57% yield).

Step C: Preparation of methyl4-(2-amino-5-bromopyridin-3-ylthio)benzoate: Placed methyl4-(2-aminopyridin-3-ylthio)benzoate (5.50 g, 21.1 mmol) in acetic acid(25 mL) and cooled to 0° C. Slowly added bromine (1.35 mL, 26.4 mmol)and stirred for an hour. Poured reaction mixture onto saturated sodiumbisulfite and ice. Extracted with dichloromethane three times, washedwith 2N NaOH, water, brine, dried, and concentrated. Subjected to MPLC(Biotage) eluting with 3:2 hexane:ethyl acetate to afford the titlecompound (4.87 g, 68.0% yield).

Step D: Preparation of methyl4-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)benzoatehydrochloride: Added methyl 4-(2-amino-5-bromopyridin-3-ylthio)benzoate(1.00 g, 2.95 mmol) to a mixture of 2-chloro-3-isothiocyanatopyridine(0.503 g, 2.95 mmol) in DMF (4 mL). Stirred at 80° C. for an hour, thenat 110° C. for 2 hours. Cooled, diluted with dichloromethane (8 mL),filtered, washed with dichloromethane, and dried to afford the titlecompound (0.625 g, 41.6% yield). ¹H NMR (ds-DMSO) δ 3.84 (s, 3H), 7.40(dd, 1H), 7.45 (d, 2H), 7.72 (d, 1H), 7.79 (bs, 1H), 7.96 (d, 2H), 8.34(d, 1H), 8.56 (s, 1H).

Example 306 Preparation of4-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-yloxy)-2-(trifluoromethyl)benzonitrile

Prepared according to the method of Example 303 using4-fluoro-2-(trifluoromethyl)benzonitrile. 1H NMR (d-DMSO) δ 7.39-7.45(m, 2H), 7.74 (s, 1H), 7.89 (d, 1H), 8.11 (s, 1H), 8.14 (d, 1H), 8.38(d, 1H), 8.52 (s, 1H).

Example 3074-(5-Bromo-2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)benzoicacid

Heated a mixture of methyl4-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)benzoatehydrochloride (0.570 g, 1.12 mmol), 1N aqueous sodium hydroxide (2.80mL, 2.80 mmol), and methanol (6 mL) at 65° C. for an hour. Cooled, andpartitioned between saturated NH₄Cl (30 mL), 1N HCl (3 mL), water (10mL) and chloroform. The mixture was filtered, washed with water, anddried to afford the title compound (0.360 g, 70.1% yield). ¹H NMR(d₆-DMSO) δ 7.35 (dd, 1H), 7.43 (d, 2H), 7.50 (s, 1H), 7.67 (d, 1H),7.94 (d, 2H), 8.44 (s, 1H).

Example 308 ethyl2-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-amino)pyridin-3-ylthio)-5-fluorobenzoatehydrochloride

Prepared according, to the method of Example 305 from ethyl5-fluoro-2-mercaptobenzoate and 3-chloro-2-nitropyridine. ¹H NMR (CDCl₃)δ 1.48 (s, 3H), 4.50 (q, 2H), 6.66 (dd, 1H), 7.07 (m, 1H), 7.32 (dd,1H), 7.81 (d, 1H), 7.86 (d, 1H), 8.07 (s, 1H), 8.42 (d, 1H), 8.61 (s,1H), 9.19 (bs, 1H).

Example 3094-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-yloxy)-3-methylbenzonitrilehydrochloride

Prepared according to the method of Example 303 using4-fluoro-3-methylbenzonitrile. ¹H NMR (d₆-DMSO) δ 2.47 (s, 3H), 7.02 (d,1H), 7.16 (s, 1H), 7.43 (dd, 1H), 7.78 (d, 1H), 7.89 (s, 1H), 7.90 (d,1H), 8.38 (d, 1H), 8.46 (s, 1H).

Example 3104-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-yloxy)-3-fluorobenzonitrilehydrochloride

Prepared according to the method of Example 303 using4-chloro-3-fluorobenzonitrile ¹H NMR (d₆-DMSO) δ 7.20 (t, 1H), 7.44 (dd,1H), 7.66 (d, 1H), 7.91 (d, 1H), 7.99 (s, 1H), 8.07 (d, 1H), 8.39 (d,1H), 8.48 (s, 1H).

Example 311 Preparation of4-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-yloxy)-3-chlorobenzonitrilehydrochloride

Prepared according to the method of Example 303 using3-chloro-4-fluorobenzonitrile. ¹H NMR (d₆-DMSO) δ 7.14 (d, 1H), 7.41(dd, 1H), 7.78 (d, 1H), 7.83 (bs, 1H), 7.93 (d, 1H), 8.23 (s, 1H), 8.36(d, 1H), 8.48 (s, 1H), 11.97 (bs, 1H).

Example 312 Preparation of3-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-yloxy)-4-chlorobenzonitrilehydrochloride

3-(2-aminopyridin-3-yloxy)-4-chlorobenzonitrile was isolated as abyproduct from step A of Example 311 and carried through the reactionsin Example 303 to afford the title compound. ¹H NMR (d₆-DMSO) δ 7.44(dd, 1H), 7.71 (d, 1H), 7.74-7.77 (m, 2H), 7.84 (d, 1H), 7.92 (m, 1H),8.39 (d, 1H), 8.43 (s, 1H).

Example 3133-methyl-N-(5-(3-methylisoxazolo[5,4-b]pyridin-4-ylthio)-3-phenoxypyrazin-2-yl)-1,2,4-thiadiazol-5-amine

Step A: Preparation of methyl3-(5-amino-6-phenoxypyrazin-2-ylthio)propanoate: Prepared according tothe method of Example from 5-Bromo-3-phenoxypyrazin-2-amine and methyl3-mercaptopropanoate.

Step B: Preparation of5-(3-methylisoxazolo[5,4-b]pyridin-4-ylthio)-3-phenoxypyrazin-2-amine:Prepared according to the method of Example 127 using methyl3-(5-amino-6-phenoxypyrazin-2-ylthio)propanoate.

Step C: Preparation of3-methyl-N-(5-(3-methylisoxazolo[5,4-b]pyridin-4-ylthio)-3-phenoxypyrazin-2-yl)-1,2,4-thiadiazol-5-amine:Prepared according to the method of Example 183, Step D to provide thetitle compound (3.9 mg, 12.7% yield). ¹H NMR (CDCl₃) δ 2.59 (s, 3H),2.64 (s, 3H), 6.88 (d, J=5 Hz, 1H), 7.06, (m, 2H), 7.26 (m, 2H), 7.34(m, 2H), 8.29 (m, 2H). Mass spectrum m/e 450.2/451.2/453.2 (M+H)⁺.

Example 314N-(5-bromo-3-(4-fluorophenoxy)pyrazin-2-yl)-3-methyl-1,2,4-thiadiazol-5-amine

Step A: Preparation of 5-bromo-3-(4-fluorophenoxy)pyrazin-2-amine:Prepared according to the method of Example 301, Step A, from3,5-dibromo-2-aminopyrazine.

Step B: Preparation ofN-(5-bromo-3-(4-fluorophenoxy)pyrazin-2-yl)-3-methyl-1,2,4-thiadiazol-5-amine:Prepared according to the method of Example 183, Step D. ¹H NMR (CDCl₃)δ 2.57 (s, 3H), 7.12-7.23 (m, 4H), 8.15 (s, 1H), 9.14 (br s, 1H). Massspectrum (ESI+) m/z 382, 384 (M+H)⁺.

Example 315 Preparation of3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoic acid

Step A: Preparation of methyl3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoate: Amixture of methyl 5-bromo-4-oxopentanoate (2.51 g, 12.0 mmol),1-(5-bromo-3-phenoxypyridin-2-yl)thiourea (3.00 g, 9.25 mmol),triethylamine (2.19 mL, 15.7 mmol), and ethanol (60 mL) was refluxed for3 hours and then stirred at ambient temperature overnight. The solventwas removed to about one third original volume and partitioned betweenCH₂Cl₂ and water. The organics were concentrated and purified on silicagel eluting with 40% EtOAc/Hexanes to give the title compound (3.22 g,80.1% yield).

Step B: Preparation of3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoic acid: Toa mixture of methyl3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoate (0.100g, 0.230 mmol) in 10 mL THF, and 5 mL water was added sodium hydroxide(0.0368 g, 0.921 mmol) and the reaction was stirred overnight. Themixture was concentrated to dryness. Water was added and washed withEt₂O and EtOAc. The aqueous was acidified with a saturated NH₄Clsolution, extracted with 3:1CH₂Cl₂-THF. The organics were dried overNa₂SO₄ and concentrated to a residue. The crude solids wererecrystallized from EtOAc/Hexanes to give the title compound (0.050 g,51.7% yield). ¹H NMR (d₆ DMSO) δ 2.58 (t, J=7.5 Hz, 2H), 2.81 (t, J=7.5Hz, 2H), 6.66 (s, 1H), 7.10 (d, J=7.8 Hz, 2H), 7.21 (t, J=7.4 Hz, 1H),7.39 (d, J=2.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 2H), 8.21 (d, J=2.0 Hz, 1H).

The following compounds were prepared from1-(5-bromo-3-phenoxypyridin-2-yl)thiourea and the corresponding1-chloroketone or 1-bromoketone, following the methods of Example 315.

Example Structure Name NMR Data 316

3-(2-(5-Bromo-3- phenoxypyridin-2- ylamino)thiazol-4-yl)- 2,2-dimethylpropanoic acid ¹H NMR (d₆ DMSO) δ 1.13 (s, 6H), 2.80 (s, 2H),6.63 (s, 1H), 7.12 (d, J = 8.0 Hz, 2H), 7.22 (t, J = 7.3 Hz, 1H), 7.36(d, J = 2.0 Hz, 1H), 7.44 (t, J = 7.9 Hz, 2H), 8.20 (d, J = 2.0 Hz, 1H).317

3-(2-(5-Bromo-3- phenoxypyridin-2- ylamino)thiazol-4-yl)-3-methylbutanoic acid ¹H NMR (d₆ DMSO) δ 1.35 (s, 6H), 2.57 (s, 2H),6.65 (s, 1H), 7.11 (d, J = 7.8 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.37(d, J = 2.0 Hz, 1H), 7.45 (t, J = 7.9 Hz, 2H), 8.21 (d, J = 2.0 Hz, 1H).318

2-(2-(5-Bromo-3- phenoxypyridin-2- ylamino)thiazol-4-yl)-2-methylpropanoic acid ¹H NMR (d₆ DMSO) δ 1.46 (s, 6H), 6.81 (s, 1H),7.10 (d, J = 7.8 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 7.39 (d, J = 2.0 Hz,1H), 7.44 (t, J = 7.9 Hz, 2H), 8.22 (d, J = 2.0 Hz, 1H), 11.03 (br s,2H), 12.17 (br s, 1H). 319

2-(2-(5-Bromo-3- phenoxypyridin-2- ylamino)thiazol-4- yl)acetic acid ¹HNMR (d₆ DMSO) δ 3.57 (s, 2H), 6.84 (s, 1H), 7.10 (d, J = 8.0 Hz, 2H),7.20 (t, J = 7.3 Hz, 1H), 7.41-7.45 (m, 3H), 8.23 (d, J = 2.0 Hz, 1H).

The following compounds were prepared from1-(5-bromo-3-phenoxypyridin-2-yl)thiourea and the corresponding1-chloroketone or 1-bromoketone, following similar methods to Example315, Step A.

Example Structure Name NMR Data 320

3-(2-(5-Bromo-3- phenoxypyridin-2- ylamino)thiazol-4- yl)propanenitrile¹H NMR (d₆ DMSO) δ 2.82-2.89 (m, 4H), 6.84 (s, 1H), 7.11 (d, J = 7.8 Hz,2H), 7.21 (t, J = 7.4 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.44 (t, J =8.0 Hz, 2H), 8.23 (d, J = 2.0 Hz, 1H), 11.02 (s, 1H). 321

4-Benzyl-N-(5-bromo- 3-phenoxypyridin-2- yl)thiazol-2-amine ¹H NMR (d₆DMSO) δ 3.92 (s, 2H), 6.66 (s, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.17-7.21(m, 2H), 7.24- 7.30 (m, 4H), 7.38 (d, J = 2.0 Hz, 1H), 7.42 (t, J = 8.0Hz, 2H), 8.21 (d, J = 2.0 Hz, 1H), 10.96 (s, 1H). 322

N-(5-Bromo-3- phenoxypyridin-2-yl)-4- (chloromethyl)thiazol- 2-amine ¹HNMR (d₆ DMSO) δ 4.70 (s, 2H), 7.11 (d, J = 7.6 Hz, 2H), 7.16 (s, 1H),7.21 (t, J = 7.4 Hz, 1H), 7.42-7.46 (m, 3H), 8.24 (d, J = 2.0 Hz, 1H),11.25 (s, 1H).

Example 323 Preparation of3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-N-methylpropanamide

A mixture of3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoic acid(0.100 g, 0.238 mmol) (Example 315) HOBT-H₂O (0.0547 g, 0.357 mmol),DIEA (d 0.742) (0.0870 mL, 0.500 mmol), EDCI (0.0684 g, 0.357 mmol), andmethanamine (0.238 mL, 0.476 mmol) in 10 mL acetonitrile was stirred atambient temperature for 5 hours and then heated at 50° C. overnight. Themixture was concentrated to a residue, dissolved in THF and precipitatedwith the addition of water. The solids were filtered, washed with waterand dried on high vacuum overnight to give the title compound (0.072 g,69.8% yield) as white solids. ¹H NMR (d₆ DMSO) δ 2.41 (t, J=7.8 Hz, 2H),2.56 (d, J=4.7 Hz, 3H), 2.79 (t, J=7.7 Hz, 2H), 6.62 (s, 1H), 7.10 (d,J=8.0 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.43 (t,J=7.9 Hz, 2H), 7.77 (d, J=4.3 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 10.94 (brs, 1H).

The following compounds were prepared from the corresponding acids(Example 322) and amines following the method of Example 323.

Example Structure Name NMR Data 324

3-(2-(5-Bromo-3- phenoxypyridin-2- ylamino)thiazol-4- yl)-N,N-dimethylpropanamide ¹H NMR (d₆ DMSO) δ 2.64 (t, J = 7.6 Hz, 2H),2.76-2.81 (m, 5H), 2.95 (s, 3H), 6.66 (s, 1H), 7.09 (d, J = 7.8 Hz, 2H),7.20 (t, J = 7.3 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.43 (t, J = 7.9 Hz,2H), 8.22 (d, J = 2.0 Hz, 1H), 10.92 (br s, 1H). 325

3-(2-(5-Bromo-3- phenoxypyridin-2- ylamino)thiazol-4-yl)-1-(pyrrolidin-1- yl)propan-1-one ¹H NMR (d₆ DMSO) δ 1.71-1.78 (m,2H), 1.81-1.88 (m, 2H), 2.58 (t, J = 7.8 Hz, 2H), 2.80 (t, J = 7.6 Hz,2H), 3.27 (t, J = 6.8 Hz, 2H), 3.38 (t, J = 6.6 Hz, 2H), 6.66 (s, 1H),1.10 (d, J = 8.0 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 7.40 (d, J = 2.0 Hz,1H), 7.43 (t, J = 7.9 Hz, 2H), 8.22 (d, J = 2.0 Hz, 1H), 10.92 (br s,1H). 326

3-(2-(5-Bromo-3- phenoxypyridin-2- ylamino)thiazol-4- yl)-N-(2-methoxyethyl) propanamide ¹H NMR (d₆ DMSO) δ 2.43 (t, J = 7.7 Hz, 2H),2.79 (t, J = 7.6 Hz, 2H), 3.18-3.27 (m, 5H), 3.30-3.32 (m, 2H), 6.62 (s,1H), 7.10 (d, J = 7.8 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 7.40 (d, J =2.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 2H), 7.93 (t, J = 5.5 Hz, 1H), 8.21(d, J = 2.0 Hz, 1H), 10.91 (br s, 1H). 327

3-(2-(5-Bromo-3- phenoxypyridin-2- ylamino)thiazol-4- yl)-N-(2-hydroxyethyl) propanamide ¹H NMR (d₆ DMSO) δ 2.42 (t, J = 7.7 Hz, 2H),2.79 (t, J = 7.5 Hz, 2H), 3.08-3.13 (m, 2H), 3.37-3.38 (m, 2H), 4.64 (brs, 1H), 6.63 (s, 1H), 7.10 (d, J = 8.0 Hz, 2H), 7.21 (t, J = 7.3 Hz,1H), 7.40 (d, J = 2.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 2H), 7.85 (t, J =5.6 Hz, 1H), 8.21 (d, J = 2.0 Hz, 1H), 10.90 (br s, 1H). 328

3-(2-(5-Bromo-3- phenoxypyridin-2- ylamino)thiazol-4- yl)-N-(2-(dimethylamino) ethyl)propanamide ¹H NMR (d₆ DMSO) δ 2.13 (s, 6H), 2.26(t, J = 6.6 Hz, 2H), 2.42 (t, J = 7.7 Hz, 2H), 2.79 (t, J = 7.6 Hz, 2H),3.10-3.15 (m, 2H), 6.63 (s, 1H), 7.10 (d, J = 7.6 Hz, 2H), 7.20 (t, J =7.4 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 2H), 7.76(t, J = 5.5 Hz, 1H), 8.21 (d, J = 2.0 Hz, 1H), 11.00 (br s, 1H). 329

2-(2-(5-Bromo-3- phenoxypyridin-2- ylamino)thiazol-4- yl)-N-methylacetamide ¹H NMR (d₆ DMSO) δ 2.58 (d, J = 4.5 Hz, 3H), 3.42 (s,2H), 6.78 (s, 1H), 7.11 (d, J = 7.8 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H),7.39 (d, J = 2.2 Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.82 (d, J = 4.3 Hz,1H), 8.22 (d, J = 2.2 Hz, 1H), 10.99 (s, 1H). 330

2-(2-(5-Bromo-3- phenoxypyridin-2- ylamino)thiazol-4- yl)-N,N-dimethylacetamide ¹H NMR (d₆ DMSO) δ 2.82 (s, 3H), 3.03 (s, 3H), 3.66(s, 2H), 6.75 (s, 1H), 7.11 (d, J = 7.8 Hz, 2H), 7.21 (t, J = 7.4 Hz,1H), 7.39 (d, J = 2.0 Hz, 1H), 7.44 (t, J = 7.9 Hz, 2H), 8.22 (d, J =2.0 Hz, 1H), 10.97 (s, 1H). 331

2-(2-(5-Bromo-3- phenoxypyridin-2- ylamino)thiazol-4-yl)-1-(pyrrolidin-1- yl)ethanone ¹H NMR (d₆ DMSO) δ 1.72-1.79 (m, 2H),1.83-1.89 (m, 2H), 3.28 (t, J = 6.8 Hz, 2H), 3.49 (t, J = 6.7 Hz, 2H),3.60 (s, 2H), 6.77 (s, 1H), 7.10 (s, 1H), 7.12 (s, 1H), 7.21 (t, J = 7.4Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.44 (t, J = 7.9 Hz, 2H), 8.22 (d, J= 2.0 Hz, 1H), 10.96 (s, 1H). 332

2-(2-(5-Bromo-3- phenoxypyridin-2- ylamino)thiazol-4- yl)-N-(2-methoxyethyl) acetamide ¹H NMR (d₆ DMSO) δ 3.21-3.23 (m, 5H), 3.32-3.35(m, 2H), 3.45 (s, 2H), 6.77 (s, 1H), 7.10 (s, 1H), 7.12 (s, 1H), 7.21(t, J = 7.4 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.44 (t, J = 7.9 Hz, 2H),7.99 (t, J = 5.4 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 10.99 (s, 1H). 333

2-(2-(5-Bromo-3- phenoxypyridin-2- ylamino)thiazol-4- yl)-N-(2-hydroxyethyl) acetamide ¹H NMR (d₆ DMSO) δ 3.10-3.27 (m, 2H), 3.37-3.42(m, 2H), 3.45 (s, 2H), 4.65 (t, J = 5.5 Hz, 1H), 6.78 (s, 1H), 7.10 (s,1H), 7.12 (s, 1H), 7.21 (t, J = 7.3 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H),7.44 (t, J = 7.9 Hz, 2H), 7.91 (br s, 1H), 8.22 (d, J = 2.0 Hz, 1H),11.00 (s, 1H). 334

2-(2-(5-Bromo-3- phenoxypyridin-2- ylamino)thiazol-4- yl)-N-(2-(dimethylamino) ethyl)acetamide ¹H NMR (d₆ DMSO) δ 2.12 (s, 6H), 2.27(t, J = 6.7 Hz, 2H), 3.12- 3.16 (m, 2H), 3.44 (s, 2H), 6.78 (s, 1H),7.10 (s, 1H), 7.12 (s, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.40 (d, J = 2.2Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.84 (t, J = 5.4 Hz, 1H), 8.22 (d, J= 2.0 Hz, 1H), 11.02 (s, 1H). 335

3-(2-(5-Bromo-3- phenoxypyridin-2- ylamino)thiazol-4- yl)-N-(2-hydroxyethyl)-2,2- dimethylpropanamide ¹H NMR (d₆ DMSO) δ 1.09 (s, 6H),2.78 (s, 2H), 3.10-3.15 (m, 2H), 3.37 (t, J = 6.1 Hz, 2H), 4.83 (br s,1H), 6.61 (s, 1H), 7.12 (d, J = 8.0 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H),7.39 (d, J = 2.1 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H), 7.57 (t, J = 5.6 Hz,1H), 8.21 (d, J = 2.0 Hz, 1H), 10.60 (br s, 1H).

Example 336 Preparation ofN-(5-bromo-3-phenoxypyridin-2-yl)-4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)thiazol-2-amine

Step A: Preparation ofN′-acetyl-3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanehydrazide:A mixture3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoic acid(0.300 g, 0.714 mmol), HOBT-H₂O (0.164 g, 1.07 mmol), DIEA (0.261 mL,1.50 mmol), EDCI (0.205 g, 1.07 mmol), and acetohydrazide (0.106 g, 1.43mmol) in 10 mL acetonitrile and 2 mL THF was stirred at 50° C. for 3hours and then overnight at ambient temperature. The mixture wasconcentrated and diluted with CH₂Cl₂, washed with saturated aqueousNaHCO₃, dried over Na₂SO₄, and concentrated to provide the titlecompound (0.431 g, 127% yield) that was carried directly on to the nextstep.

Step B: Preparation of5-bromo-N-(4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)thiazol-2-yl)-3-phenoxypyridin-2-amine:To a mixture ofN′-acetyl-3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanehydrazide(0.100 g, 0.210 mmol) in 5 mL acetonitrile was added POCl₃ (0.0769 mL,0.840 mmol) and the reaction was heated at 50° C. for 72 hours. Themixture was concentrated to dryness, diluted with water and extractedwith CH₂C₂. The organic layer was dried over Na₂SO₄ and purified bypreparative HPLC to give the title compound (0.029 g, 30.1% yield). ¹HNMR (d₆ DMSO) δ 2.50 (2, 3H), 3.00 (t, J=7.4 Hz, 2H), 3.17 (t, J=7.5 Hz,2H), 6.76 (s, 1H), 7.11 (d, J=7.6 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.40(d, J=2.0 Hz, 1H), 7.44 (t, J=7.9 Hz, 2H), 8.22 (d, J=2.2 Hz, 1H), 10.99(s, 1H).

The following compounds were-prepared from the corresponding acid(Example 315) and corresponding acylhydrazine following the method ofExample 336.

Example Structure Name NMR Data 337

N-(5-Bromo-3- phenoxypyridin-2- yl)-4-((5-methyl- 1,3,4-oxadiazol-2-yl)methyl)thiazol- 2-amine ¹H NMR (d₆ DMSO) δ 2.44 (s, 3H), 4.21 (s,2H), 6.97 (s, 1H), 7.08 (s, 1H), 7.10 (s, 1H), 7.20 (t, J = 7.4 Hz, 1H),7.40-7.45 (m, 3H), 8.23 (d, J = 2.0 Hz, 1H), 11.14 (s, 1H). 338

N-(5-Bromo-3- phenoxypyridin-2- yl)-4-(2-(5- isopropyl-1,3,4-oxadiazol-2- yl)ethyl)thiazol-2- amine ¹H NMR (d₆ DMSO) δ 1.25 (d, J =6.8 Hz, 6H), 3.00 (t, J = 7.5 Hz, 2H), 3.09-3.14 (m, 1H), 3.18 (t, J =7.5 Hz, 2H), 6.73 (s, 1H), 7.10 (d, J = 7.8 Hz, 2H), 7.21 (t, J = 7.3Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H), 8.22 (d, J= 2.0 Hz, 1H), 10.98 (s, 1H). 339

N-(5-Bromo-3- phenoxypyridin-2- yl)-4-(2-methyl-2- (5-methyl-1,3,4-oxadiazol-2- yl)propyl)thiazol- 2-amine ¹H NMR (d₆ DMSO) δ 1.36 (s, 6H),2.44 (s, 3H), 2.95 (s, 2H), 7.12 (d, J = 7.8 Hz, 2H), 7.22 (t, J = 6.8Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 8.20 (d, J= 2.0 Hz, 1H), 10.78 (s, 1H).

Example 340 Preparation ofN-(5-bromo-3-phenoxypyridin-2-yl)-4-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)thiazol-2-amine

To a mixture of3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoic acid(0.100 g, 0.238 mmol), DIEA (0.0456 mL, 0.262 mmol) in 5 mL DMF atambient temperature was addedN-((dimethylamino)fluoromethylene)-N-methylmethanaminiumhexafluorophosphate(V) (0.0628 g, 0.238 mmol). The mixture was stirredfor 30 minutes at ambient temperature and then N-hydroxyacetamidine(0.0194 g, 0.262 mmol) was added in one portion and the reaction washeated at 110° C. overnight. The reaction was then cooled to ambienttemperature and EtOAc was added and the organic layer washed with water(2×10 mL), dried over Na₂SO₄ and concentrated to a residue that waspurified on silica gel eluting with 25% EtOAc/Hexanes to give 5 thetitle compound (0.067 g, 61.4% yield). ¹H NMR (d₆ DMSO) δ 2.29 (s, 3H),3.04 (t, 7.6 Hz, 2H), 3.26 (t, J=7.6 Hz, 2H), 6.74 (s, 1H), 7.11 (d,J=7.8 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.44 (t,J=8.0 Hz, 2H), 8.22 (d, J=2.0 Hz, 1H), 11.00 (s, 1H).

Example 341N-(5-Bromo-3-phenoxypyridin-2-yl)-4-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)thiazol-2-amine

Prepared from the corresponding acid (Example 314) following the methodof Example 340. ¹H NMR (d₆ DMSO) δ 2.29 (s, 3H), 4.29 (s, 2H), 7.00 (s,1H), 7.08 (s, 1H), 7.10 (s, 1H), 7.20 (t, J=7.3 Hz, 1H), 7.41-7.45 (m,3H), 8.23 (d, J=2.0 Hz, 1H), 11.13 (s, 1H).

Example 342 Preparation ofN-(5-bromo-3-phenoxypyridin-2-yl)-4-(2-(5-methyloxazol-2-yl)ethyl)thiazol-2-amine

Step A: Preparation of3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-N-(2-oxopropyl)propanamide:A mixture of3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoic acid(0.800 g, 1.90 mmol), HOBT-H₂O (0.437 g, 2.86 mmol), DIEA (1.36 mL, 7.80mmol), EDCI (0.547 g, 2.86 mmol), and 1-aminopropan-2-one hydrochloride(0.834 g, 7.61 mmol) in 50 mL THF was stirred at 50° C. for 2 days. Themixture was concentrated and diluted with CH₂Cl₂ and washed with water,dried over sodium sulfate and concentrated to a residue that was carriedon to the next step without further purification.

Step B: Preparation of5-bromo-N-(4-(2-(5-methyloxazol-2-yl)ethyl)thiazol-2-yl)-3-phenoxypyridin-2-aminehydrochloride: Prepared according to the method of Example 336, Step B(0.043 g, 12.2% yield). ¹H NMR (d₆ DMSO) δ 2.25 (s, 3H), 3.00-3.08 (m,4H), 6.72 (s, 1H), 6.81 (s, 1H), 7.14 (d, J=7.8 Hz, 2H), 7.23 (t, J=7.4Hz, 1H), 7.43-7.47 (m, 3H), 8.25 (d, J=2.0 Hz, 1H).

Example 343 N-(5Bromo-3-phenoxypyridin-2-yl)-4-((5-methyloxazol-2-yl)methyl)thiazol-2-amine

The following compound was prepared from the corresponding acid (Example315) following the method of Example 342. ¹H NMR (d₆DMSO) δ 2.22 (d,J=1.0 Hz, 3H), 4.05 (s, 2H), 6.71 (d, J=1.2 Hz, 1H), 6.86 (s, 1H), 7.09(d, J=7.8 Hz, 2H), 7.20 (t, J=7.4 Hz, 1H), 7.40-7.45 (m, 3H), 8.22 (d,J=2.2 Hz, 1H), 11.09 (s, 1H).

Example 344 Preparation of4-(2-(1H-tetrazol-5-yl)ethyl)-N-(5-bromo-3-phenoxypyridin-2-yl)thiazol-2-amine

To a nitrogen purged vial was added TBAF (0.249 mL, 0.249 mmol),3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanenitrile(0.200 g, 0.498 mmol) (Example 320), and TMSN₃ (0.0992 mL, 0.748 mmol)were added, and the reaction was stirred at 120° C. for 24 Hr. The crudereaction mixture was dissolved in CH₂Cl₂ and washed with aqueous sodiumbicarbonate solution. The organic layer was concentrated to a residuethat was purified on silica gel by eluting with 7% MeOH/CH₂Cl₂ andfurther purified by triturating in refluxing EtOAc to give the titlecompound (0.128 g, 57.8% yield). ¹H NMR (d₆ DMSO) δ 3.03 (t, J=7.5 Hz,2H), 3.25 (t, J=7.6 Hz, 2H), 6.70 (s, 1H), 7.13 (d, J=8.0 Hz, 2H), 7.22(t, J=7.3 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.45 (t, J=7.9 Hz, 2H), 8.22(d, J=2.2 Hz, 1H), 11.01 (s, 1H).

Example 345 Preparation ofN-(5-bromo-3-phenoxypyridin-2-yl)-4-(phenoxymethyl)thiazol-2-amine

Phenol (0.0356 g, 0.378 mmol) was dissolved in 3 mL THF at ambienttemperature. NaH (0.00907 g, 0.378 mmol) was added and the mixturestirred for 30 minutes at ambient temperature. SolidN-(5-Bromo-3-phenoxypyridin-2-yl)-4-(chloromethyl)thiazol-2-amine (0.030g, 0.0756 mmol) (Example 322) was then added to the reaction and themixture was stirred at ambient temperature overnight. The reaction wasconcentrated to dryness, dissolved in CH₂Cl₂, washed with water, driedover Na₂SO₄, and concentrated to dryness. The residue was purified bypreparative HPLC to give the title compound (0.007 g, 20.4% yield) asthe least polar of the two major products. ¹H NMR (CDCl₃) δ 5.07 (s,2H), 6.88 (s, 1H), 6.96 (t, J=7.3 Hz, 1H), 7.01 (d, J=8.0 Hz, 2H), 7.07(d, J=8.8 Hz, 2H), 7.14 (d, J=2.0 Hz, 1H), 7.23-7.31 (m, 3H), 7.43 (t,J=8.0 Hz, 2H), 8.14 (d, J=2.0 Hz, 1H), 8.76 (br s, 1H).

The following compounds were prepared from the corresponding phenols andthiophenols andN-(5-Bromo-3-phenoxypyridin-2-yl)-4-(chloromethyl)thiazol-2-amine(Example 322) following the method of Example 345.

Example Structure Name NMR Data 346

N-(5-Bromo-3- phenoxypyridin- 2-yl)-4-((5- methyl-1,3,4- oxadiazol-2-ylthio)methyl) thiazol-2-amine ¹H NMR (CDCl₃) δ 2.37 (s, 3H), 4.46 (s,2H), 7.04 (s, 1H), 7.11 (d, J = 8.2 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H),7.42-7.46 (m, 3H), 8.23 (d, J = 1.8 Hz, 1H), 11.19 (s, 1H). 347

5-Bromo-N-(4- ((1-methyl-3- (trifluoromethyl)- 1H-pyrazol-5-yloxy)methyl) thiazol-2-yl)-3- phenoxypyridin- 2-amine ¹H NMR (d₆ DMSO)δ 3.62 (s, 3H), 3.74 (s, 2H), 6.47 (br s, 1H), 7.15 (d, J = 7.8 Hz, 2H),7.24 (t, J = 7.4 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.46 (t, J = 7.9 Hz,2H), 8.21 (d, J = 2.0 Hz, 1H), 11.21 (br s, 1H), 11.36 (br s, 1H).

Example 348 Preparation ofN-(5-bromo-3-phenoxypyridin-2-yl)-4-((phenylamino)methyl)thiazol-2-amine

Aniline (0.0352 g, 0.378 mmol) was dissolved in 2 mL NMP at ambienttemperature. Cs₂CO₃ (0.0246 g, 0.0756 mmol) and solid5-bromo-N-(4-(chloromethyl)thiazol-2-yl)-3-phenoxypyridin-2-amine (0.030g, 0.0756 mmol) were added to the reaction and the mixture was stirredat ambient temperature overnight. The reaction was concentrated todryness, dissolved in CH₂Cl₂, washed with water, dried over Na₂SO₄, andconcentrated to dryness. The residue was purified by preparative HPLC togive the title compound (0.010 g, 29.2% yield) as tan solids. ¹H NMR(CDCl₃) δ 4.34 (br s, 3H), 6.67-6.74 (m, 4H), 7.07 (d, J=8.0 Hz, 2H),7.13 (d, J=1.8 Hz, 1H), 7.18 (t, J=7.7 Hz, 2H), 7.24-7.27 (m, 1H), 7.43(t, J=7.9 Hz, 2H), 8.13 (d, J=1.6 Hz, 1H), 8.74 (br s, 1H).

The following compounds were prepared from the corresponding amines andN-(5-Bromo-3-phenoxypyridin-2-yl)-4-(chloromethyl)thiazol-2-amine(Example 322) following the method of Example 348.

Example Structure Name NMR Data 349

N-((2-(5-Bromo-3- phenoxypyridin-2- ylamino)thiazol-4- yl)methyl)-5-methyl-1,3,4- oxadiazol-2-amine ¹H NMR (d₆ DMSO) δ 2.12 (s, 3H), 4.71(s, 2H), 6.12 (s, 1H), 6.89 (s, 1H), 7.11 (d, J = 7.8 Hz, 2H), 7.21 (t,J = 7.3 Hz, 1H), 7.40-7.46 (m, 3H), 8.23 (d, J = 2.1 Hz, 1H), 11.13 (s,1H). 350

N-(5-Bromo-3- phenoxypyridin-2- yl)-4-(pyrrolidin-1- ylmethyl)thiazol-2-amine ¹H NMR (d₆ DMSO) δ 1.72 (br s, 4H), 2.63 (br s, 4H), 3.69 (br s,2H), 6.88 (s, 1H),7.10 (s, 1H), 7.12 (s, 1H), 7.21 (t, J = 7.3 Hz, 1H),7.41-7.46 (m, 3H), 8.22 (d, J = 2.0 Hz, 1H), 11.04 (br s, 1H).

Example 351 Preparation of5-bromo-3-phenoxy-N-(4-(phenylthiomethyl)thiazol-2-yl)pyridin-2-aminehydrochloride

Prepared according to the method of Example 345 using5-bromo-N-(4-(chloromethyl)thiazol-2-yl)-3-phenoxypyridin-2-amine andbenzenethiol. ¹H NMR (CDCl₃) δ 4.13 (s, 2H), 6.48 (s, 1H), 7.19 (d,J=8.0 Hz, 2H), 7.26-7.32 (m, 5H), 7.38 (d, J=7.0 Hz, 2H), 7.44 (t, J=7.6Hz, 2H), 8.12 (d, J=1.6 Hz, 1H), 12.71 (s, 1H).

Example 352 Preparation of5-(2-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)ethyl)-1,3,4-oxadiazol-2-ol

Step A: Preparation of3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanehydrazide:To a mixture of methyl3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoate (1.00g, 2.303 mmol) (Example 315) in 15 mL EtOH was added hydrazinemonohydrate (8.835 mL, 11.51 mmol) and the mixture heated at 75° C. for4 hours. The reaction was cooled to ambient temperature and quenchedwith water and the solids were filtered to give the title compound(0.831 g, 83.10% yield) as off white solids there were used withoutfurther purification.

Step B: Preparation of5-(2-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)ethyl)-1,3,4-oxadiazol-2-ol:To a mixture of3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanehydrazide(0.150 g, 0.345 mmol) in THF (5 mL) was added TEA (0.04814 mL, 0.3454mmol) and cooled in an ice bath. To this mixture was added. CDI (0.0672g, 0.414 mmol) in one portion. The mixture was allowed to warm toambient temperature and was then heated at 50° C. overnight. Thereaction was concentrated to dryness, dissolved in CH₂Cl₂ and washedwith water, dried over Na₂SO₄, concentrated to a residue that waspurified by preparative HPLC to give the title compound (0.045 g, 28.31%yield) was white solids. ¹H NMR (d₆ DMSO) δ 2.91 (s, 4H), 6.75 (s, 1H),7.10 (d, J=7.8 Hz, 2H), 7.21 (t, J=7.4 Hz, 1H), 7.40 (d, J=2.1 Hz, 1H),7.44 (t, J=7.9 Hz, 2H), 8.22 (d, J=2.1 Hz, 1H), 11.03 (br s, 1H), 12.04(br s, 1H).

Example 353 Preparation ofN-(5-bromo-3-phenoxypyridin-2-yl)-4-(2-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)thiazol-2-amine

Step A: Preparation of(Z)-3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-N′-hydroxypropanamidine:To a mixture of3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanenitrile(1.00 g, 2.49 mmol) (Example 320) in 150 mL EtOH was added a mixture ofhydroxylamine hydrochloride (0.866 g, 12.5 mmol) and NaOH (12.5 mL, 12.5mmol) and the combined mixture was heated at reflux overnight. To thereaction was then added hydroxylamine hydrochloride (0.866 g, 12.5 mmol)and 1N NaOH (12.5 mL, 12.5 mmol) and the reaction reluxed overnight. Themixture was cooled, concentrated to a residue, diluted with CH₂Cl₂ and1N HCl, the aqueous layer was made basic with NH₄OH and extracted withCH₂Cl₂. The basic organic extracts were dried on Na₂SO₄, filtered andconcentrated to give the title compound (1.02 g, 94.2% yield).

Step B: Preparation of(Z)—N′-acetoxy-3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanimidamide:To a suspension of(Z)-3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-N′-hydroxypropanamidine(0.200 g, 0.460 mmol) and K₂CO₃ (0.070 g, 0.506 mmol) in acetone (5 mL),cooled in an ice bath, was added a solution of acetyl chloride (0.032mL, 0.460 mmol) in 3 mL acetone and the mixture was allowed to slowlywarm to ambient temperature. The reaction was concentrated to dryness,dissolved in CH₂Cl₂ and washed with water, dried over Na₂SO₄, andconcentrated to give the title compound (0.205 g, 93.4% yield) that wasused without further purification.

Step C: Preparation of5-bromo-N-(4-(2-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)thiazol-2-yl)-3-phenoxypyridin-2-amine:The(Z)—N′-acetoxy-3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanimidamide(0.050 g, 0.10 mmol) was heated (neat) at 150° C. under high vacuum for3 hrs. The crude reaction residue was then purified by preparative HPLCto give the title compound (0.015 g, 31% yield) as a white solid. ¹H NMR(d₆ DMSO) δ 2.55 (s, 3H), 2.97-3.05 (m, 41H), 6.72 (s, 1H), 7.11 (d,J=7.8 Hz, 2H), 7.21 (t, J=7.4 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.44 (t,J=7.9 Hz, 2H), 8.22 (d, J=2.0 Hz, 1H), 11.00 (s; 1H).

Example 354 Preparation ofN-(5-bromo-3-(phenylthio)pyridin-2-yl)-4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)thiazol-2-amine

Step A: Preparation of methyl3-(2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)propanoate: Amixture of methyl 5-bromo-4-oxopentanoate (1.20 g, 5.73 mmol),1-(5-bromo-3-(phenylthio)pyridin-2-yl)thiourea (1.50 g, 4.41 mmol)(Example 179), triethylamine (1.04 mL, 7.49 mmol), and MeOH (25 mL) wasrefluxed overnight. The reaction was concentrated to a residue andpartitioned between CH₂Cl₂ and water. The organics were concentrated toa residue and triturated in refluxing EtOAc and the solids filtered(solids are acid). The filtrate was concentrated and purified on silicagel eluting with 30% EtOAc/Hexanes to the title compound (1.43 g, 72.0%yield).

Step B: Preparation of3-(2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)propanoicacid: To a mixture of methyl3-(2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)propanoate(1.40 g, 3.11 mmol) in 50 mL THF was added 25 mL water followed bysodium hydroxide (0.249 g, 6.22 mmol) and the mixture was stirredovernight. The mixture was concentrated to dryness, water added andacidified with NH₄C1. The mixture was then extracted with THF. Theorganics were dried over Na₂SO₄ and concentrated to give the titlecompound (1.38 g, 102% yield) that was used as the crude material.

Step C: Preparation ofN′-acetyl-3-(2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)propanehydrazide:Prepared according to the method of Example 336, Step A.

Step D: Preparation of5-bromo-N-(4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)thiazol-2-yl)-3-(phenylthio)pyridin-2-amine:Prepared according to the method of Example 336, Step B. ¹H NMR (CDCl₃)δ 2.48 (s, 3H), 3.09-3.22 (m, 4H), 6.53 (s, 1H), 7.19-7.26 (m, 3H),7.29-7.32 (m, 2H), 7.92 (d, J=2.1 Hz, 1H), 8.42 (d, J=2.1 Hz, 1H), 8.98(br s, 1H).

Example 355 Preparation ofN-(5-bromo-3-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)-3-(tetrahydrofuran-2-yl)-1,2,4-thiadiazol-5-amine

Step A: Preparation of3-(2-bromo-4-(trifluoromethyl)phenoxy)pyridin-2-amine: A mixture of2-aminopyridin-3-ol (1.00 g, 9.08 mmol) and DMF (20 mL) was cooled in a0° C. bath and sodium hydride (0.240 g, 9.49 mmol) was slowly added inportions with vigorous stirring (significant gas evolution). After theaddition was completed, the mixture was stirred at ambient temperaturefor 30 minutes to ensure all the NaH was consumed (reaction becomes veryviscous). The 2-bromo-1-fluoro-4-(trifluoromethyl)benzene (1.17 mL, 8.26mmol) was added and the mixture heated to 110° C. under nitrogenovernight. The reaction was cooled to ambient temperature and the DMFremoved under reduced pressure. The resulting black sludge was quenchedwith 0.5 N NaOH (100 mL) and extracted with Et₂O). The organic layer waswashed with 1N NaOH and brine, dried over sodium sulfate, filtered andconcentrated to afford a brown solid. The solids were purified on silicagel eluting with 40% EtOAc/Hexanes to afford3-(2-bromo-4-(trifluoromethyl)phenoxy)pyridin-2-amine the titlecompound.

Step B: Preparation of 3-(4-(trifluoromethyl)phenoxy)pyridin-2-amine:Step B: Preparation of 3-(4-(trifluoromethyl)phenoxy)pyridin-2-amine: A500 mL parr shaker was charged with3-(2-bromo-4-(trifluoromethyl)phenoxy)pyridin-2-amine (1.85 g, 5.55mmol), NaOAc (0.911 g, 11.1 mmol) and EtOH (100 mL), purged withnitrogen and Pd(OH)₂/C (0.200 g, 1.42 mmol) was added and a pressure of30 psi Hydrogen was maintained. After 2 hours, the mixture was filteredthrough GFF paper and the filtrate concentrated to a residue. Theresidue was dissolved in EtOAc, washed with a sodium bicarbonatesolution, dried over Na₂SO₄, filtered, concentrated to a residue andpurified on silica gel by eluting with 50% EtOAc/Hexanes to give thetitle compound (1.24 g, 87.8% yield) as a white solid.

Step C: Preparation of5-bromo-3-(4-(trifluoromethyl)phenoxy)pyridin-2-amine: A 250 mLround-bottomed flask was charged with3-(4-(trifluoromethyl)phenoxy)pyridin-2-amine (1.24 g, 4.88 mmol) andCHCl₃ (150 mL), cooled to 0° C. and bromine (0.275 mL, 5.37 mmol) wasadded dropwise. The reaction was stirred for 60 minutes. The reactionwas quenched into a saturated aqueous NaHCO₃ solution and extracted withCH₂Cl₂ (2×150 mL). The combined organics were dried over sodium sulfate,filtered and concentrated. The residue was purified on silica geleluting with 20% EtOAc/hexanes. The combined fractions of product weretreated with charcoal, filtered through GFF paper and concentrated toafford the title compound (0.850 g, 52.3% yield) as a tan solid.

Step D: Preparation of5-bromo-N-(3-(tetrahydrofuran-2-yl)-1,2,4-thiadiazol-5-yl)-3-(4-(trifluoromethyl)phenoxy)pyridin-2-amine:Prepared according to the method of Example 183, Step D. ¹H NMR (d₆DMSO) δ 2.21-2.27 (m, 2H), 3.54-3.61 (m, 1H), 3.74-3.86 (m, 3H), 4.03(t, J=8.0 Hz, 1H), 7.23 (d, J=8.6 Hz, 2H), 7.76 (d, J=8.8 Hz, 2H), 7.94(d, J=2.0 Hz, 1H), 8.48 (d, J=2.0 Hz, 1H), 12.37 (s, 1H).

Example 356 Preparation ofN-(5-(pyridin-2-ylthio)-3-(4-(trifluoromethyl)phenoxy)pyridin-2-(tetrahydrofuran-2-yl)-1,2,4-thiadiazol-5-amine

Prepared from5-bromo-N-(3-(tetrahydrofuran-2-yl)-1,2,4-thiadiazol-5-yl)-3-(4-(trifluoromethyl)phenoxy)pyridin-2-amineaccording to the method of Example 162, Step A. ¹H NMR (d₆ DMSO) δ2.23-2.28 (m, 2H), 3.56-3.63 (m, 1H), 3.75-3.80 (m, 1H), 3.82-3.88 (m,2H), 4.04 (t, J=8.0 Hz, 1H), 7.15-7.19 (m, 2H), 7.26 (d, J=8.6 Hz, 2H),7.66-7.70 (m, 1H), 7.76 (d, J=8.6 Hz, 2H), 7.85 (d, J=2.0 Hz, 1H), 8.40(d, J=4.7 Hz, 1H), 8.50 (d, J=1.8 Hz, 1H), 12.50 (s, 1H).

Example 357 Preparation ofN-(4-(2-(5-methyloxazol-2-ethylthiazol-2-yl-3-phenoxy-5-(thieno[32-b]pyridin-7-ylthio)pyridin-2-aminedihydrochloride

Prepared according to the method of Example 211, Steps A and B, using5-bromo-N-(4-(2-(5-methyloxazol-2-yl)ethyl)thiazol-2-yl)-3-phenoxypyridin-2-amineas the starting material. ¹H NMR (d₆-DMSO) δ 8.63 (d, 1H), 8.44 (m, 2H),7.75 (d, 1H), 7.52 (d, 1H), 7.40 (m, 2H), 7.17 (m, 4H), 6.83 (s, 1H),6.72 (m, 1H), 3.11-2.99 (m, 4H), 2.25 (d, 3H). Mass spectrum (apci)m/z=543.5 (M+H-2HCl).

Example 358 Preparation of4-(2-(5-methyloxazol-2-yl)ethyl)-N-(3-phenoxy-5-(piperidin-4-ylmethylthio)pyridin-2-yl)thiazol-2-aminedihydrochloride

Prepared according to the method of Example 34. ¹H NMR (d₆-DMSO) δ 11.40(bs, 1H), 8.95 (m, 1H), 8.65 (m, 1H), 8.18 (m, 1H), 7.44 (t, 2H), 7.36(s, 1H), 7.21 (t, 1H), 7.12 (d, 2h), 6.83 (s, 1H), 6.72 (s, 1H), 3.20(m, 2H), 3.04 (m, 4H), 2.87 (d, 2H), 2.78 (m, 2H), 2.24 (s, 3H), 1.87(m, 2H), 1.67 (m, 1H), 1.36 (m, 2H). Mass spectrum (apci) m/z=507.5(M+H-2HCl).

Example 359N-(5-bromo-3-(4-fluorophenylthio)pyridin-2-yl)thiazolo[5,4-b]pyridin-2-aminehydrochloride

Step A: Preparation of 3-(4-fluorophenylthio)-2-nitropyridine: Preparedaccording to the method of Example 180, Step A using3-chloro-2-nitropyridine and 4-fluorobenzenethiol.

Steps B and C: Preparation ofN-(5-bromo-3-(4-fluorophenylthio)pyridin-2-yl)thiazolo[5,4-b]pyridin-2-aminehydrochloride: Prepared according to the method of Example 181, Steps Band C. ¹H NMR (CDCl₃) δ 7.05 (t, 2H), 7.27-7.32 (m, 2H), 7.32-7.36 (m,1H), 7.90-7.94 (m, 2H), 8.43 (dd, 1H), 8.49 (d, 1H).

Example 360 Methyl3-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)benzoatehydrochloride

Prepared according to the method of Example 359. ¹H NMR (CDCl₃) δ 3.91(s, 3H), 7.31-7.39 (m, 3H), 7.88-7.92 (m, 3H), 8.0 (s, 1H), 8.43 (d,1H), 8.54 (s, 1H), 9.14 (bs, 1H).

Example 361N-(3-(1-methyl-1H-imidazol-2-ylthio)pyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine

Step A: Preparation of 3-(1-methyl-1H-imidazol-2-ylthio)pyridin-2-amine:3-(1-methyl-1H-imidazol-2-ylthio)-2-nitropyridine (prepared according tothe procedure of Example 359 (2.2 g, 9.3 mmol) was dissolved in aceticacid (30 mL) and cooled in a water bath. Zn dust (<10 micron, 3.0 g, 47mmol) was slowly added in portions and the reaction stirred at ambienttemperature for 30 minutes. The solution was filtered through celite(rinsing with dichloromethane) and the filtrate was concentrated. Thesolution was neutralized with NH₄OH solution and extracted with EtOAc.The organic layer was dried and concentrated to provide the titlecompound (1.8 g, 94% yield) as a dark brown solid.

Step B: Preparation ofN-(3-(1-methyl-1H-imidazol-2-ylthio)pyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine:Prepared according to the method of Example 181 using2-chloro-3-isothiocyanatopyridine. ¹H NMR (CDCl₃) δ 3.77 (s, 3H),6.92-6.96 (m, 1H), 7.00 (s, 1H), 7.20 (s, 1H), 7.32 (dd, 1H), 7.88 (d,1H), 8.00 (d, 1H), 8.40 (d, 2H), 10.80 (bs, 1H).

Example 3625-bromo-3-(4-fluorophenylthio)-N-(4-methylthiazol-2-yl)pyridin-2-amine

Prepared according to the method of Example 7, Steps C, D and E, from5-bromo-3-(4-fluorophenylthio)pyridin-2-amine. ¹H NMR (CDCl₃) δ 2.33 (s,3H), 6.44 (s, 1H), 7.01 (t, 2H), 7.23 (dd, 2H), 7.87 (d, 1H), 8.40 (d,1H).

The following compounds were also prepared following the procedure ofExample 362.

Example R² Name Data 363

Methyl 2-(5-bromo-2-(4- methylthiazol-2- ylamino)pyridin-3-ylthio)-1-methyl-1H-imidazole-5- carboxylate. ¹H NMR (CDCl₃) δ 2.36 (s, 3H), 3.84(s, 3H), 4.00 (s, 3H), 6.43 (s, 1H), 7.73 (s, 1H), 7.94 (s, 1H), 8.40(s, 1H). 364

5-bromo-N-(4-methylthiazol- 2-yl)-3-(pyrimidin-2- ylthio)pyridin-2-amine¹H NMR (CDCl₃) δ 2.31 (s, 3H), 6.44 (s, 1H), 7.04 (t, 1H), 8.00 (s, 1H),8.47- 8.49 (m, 3H), 8.85 (bs, 1H).

Example 3653-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)benzoicacid

Prepared according to the method of Example 45 from methyl3-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)benzoate.¹H NMR (DMSO-d₆) δ 7.37-7.42 (m, 1H), 7.61 (t, 1H), 7.72 (bs, 2H), 7.96(bs, 3H), 8.32 (dd, 1H), 8.42 (bs, 1H).

Example 3663-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)-N-(2-(dimethylamino)ethyl)benzamide

3-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)benzoicacid (0.080 g, 0.17 mmol) and N1,N1-dimethylethane-1,2-diamine (0.020 g,0.23 mmol) were dissolved in DMF.1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.037 g,0.19 mmol) and HOBT-H₂O (0.029 g, 0.19 mmol) were then added.N,N-Diisopropylethylamine (0.034 mL, 0.19 mmol) was added last. Thereaction was stirred at ambient temperature for 2 days. The material wasdiluted with water and the solid was filtered and recrystallized inEtOAc/hexanes to afford the title compound (0.030 g, 33% yield) as awhite solid. ¹H NMR (CDCl₃) δ 2.25 (s, 6H), 2.50 (t, 2H), 3.46-3.51 (m;2H), 6.91 (bs, 1H), 7.28-7.37 (m, 3H), 7.62 (d, 1H), 7.68 (s, 1H), 7.86(d, 1H), 7.97 (s, 1H), 8.41 (d, 1H), 8.48 (s, 1H).

The following compounds were also prepared following the procedure ofExample 366.

Example R² Name Data 367

(4-(5-bromo-2- (thiazolo[5,4-b]pyridin-2- ylamino)pyridin-3-ylthio)phenyl)(4- methylpiperazin-1- yl)methanone. ¹H NMR (CDCl₃) δ 2.25(s, 3H), 2.23- 2.38 (m, 2H), 2.40-2.50 (m, 2H), 3.37-3.43 (m, 2H),3.70-3.82 (m, 2H), 7.19 (d, 2H), 7.28-7.36 (m, 3H), 7.89 (d, 1H), 8.04(d, 1H), 8.43 (d, 1H), 8.55 (d, 1H), 9.17 (bs, 1H). 368

4-(5-bromo-2- (thiazolo[5,4-b]pyridin-2- ylamino)pyridin-3-ylthio)-N-(2- (dimethylamino)ethyl) benzamide ¹H NMR (CDCl₃) δ 2.27 (s, 6H),2.54 (bs, 2H), 3.49-3.51 (m, 2H), 6.94 (bs, 1H), 7.18 (d, 2H), 7.32 (t,1H), 7.73 (d, 2H), 7.87 (d, 1H), 8.02 (s, 1H), 8.42 (s, 1H), 8.55 (s,1H).The following compounds were also prepared following the procedure ofExample 366.

Example R² Name Data 369

2-(5-bromo-2-(4- methylthiazol-2- ylamino)pyridin-3-ylthio)- N-(2-(dimethylamino)ethyl)-1- methyl-1H-imidazole-5- carboxamide ¹H NMR(CDCl₃) δ 2.23 (s, 6H), 2.37 (s, 3H), 2.46 (t, 2H), 3.40- 3.44 (m, 2H),4.00 (s, 3H), 6.42 (s, 1H), 6.60 (s, 1H), 7.47 (s, 1H), 7.91 (s, 1H),8.37 (s, 1H). 370

3-(5-bromo-2-(4-methyl- thiazol-2-ylamino) pyridin-3-ylthio)-N-(2-(dimethylamino)ethyl) benzamide. ¹H NMR (CDCl₃) δ 2.31 (s, 3H), 2.36 (s,6H), 2.62 (bs, 2H), 3.54- 3.56 (m, 2H), 6.44 (s, 1H), 7.24- 7.35 (m,3H), 7.66 (s, 2H), 7.96 (s, 1H), 8.44 (s, 1H).

Example 371(2-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)-1-methyl-1H-imidazol-5-yl)methanol

Methyl2-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)-1-methyl-1H-imidazole-5-carboxylate(0.076 g, 0.17 mmol) dissolved in THF (5 mL) was cooled to 0° C. DIBAL-H(1M in hexanes, 0.52 mL, 0.52 mmol) was added. After 15 minutes, DIBAL-H(0.52 mL, 0.52 mmol) was added again. The solution was diluted with asaturated solution of Rochelle's Salt (10 mL) and the solution stirredovernight. The material was extracted with dichloromethane and theorganic layer was dried, and concentrated. Reverse phase HPLCpurification gave the title compound (0.006 g, 9% yield) as a whitesolid. ¹H NMR (DMSO-d₆) δ 2.18 (s, 3H), 3.64 (s, 3H), 4.50 (d, 2H), 5.22(t, 1H), 5.75 (s, 1H), 6.38 (bs, 1H), 7.11 (s, 1H), 8.22 (bs, 1H).

Example 3723-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)benzoic acid

Prepared from 3-(5-bromo-2-thioureidopyridin-3-ylthio)benzoic acidaccording to the method of Example 7, Steps C, D and E. ¹H NMR (DMSO-d₆)δ 2.17 (s, 3H), 6.44 (s, 1H), 7.40 (s, 1H), 7.56-7.66 (m, 3H), 7.90-7.95(m, 2H), 8.32 (s, 1H), 12.40 (bs, 1H).

Example 3733-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)benzamide

3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)benzoic acid(0.35 g, 0.83 mmol) was dissolved in DMF (5 mL).1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.24 g, 1.2mmol), NH₄Cl (0.133 g, 2.5 mmol) and HOBT-H₂O (0.19 g, 1.2 mmol) wereadded. Triethylamine (0.29 mL, 2.1 mmol) was added last. The reactionstirred at room temperature overnight. The material was diluted withwater and the solid was filtered to give the title compound (0.23 g, 67%yield). ¹H NMR (DMSO-d₆) δ 2.17 (s, 3H), 6.40 (bs, 1H), 7.48 (s, 1H),7.53-7.56 (m, 2H), 7.90-7.96 (m, 2H), 8.08 (s, 1H), 8.27 (bs, 1H).

Example 3743-(5-Bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)benzonitrile

3-(5-Bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)benzamide (0.20g, 0.48 mmol) was suspended in acetonitrile (4 mL). POCl₃ (0.11 mL, 1.2mmol) was added and the reaction stirred in a sealed tube at 70° C. for4 hours. The solution was cooled and neutralized with saturated NaHCO₃solution. The material was extracted with EtOAc, dried, andconcentrated. The crude material was triturated with ether/EtOAc andfiltered. The solid was dried to give the title compound (0.065 g, 34%).¹H NMR (DMSO-d₆) δ 2.17 (s, 3H), 6.44 (bs, 1H), 7.58-7.68 (m, 3H), 7.83(d, 1H), 7.92 (s, 1H), 8.36 (s, 1H).

Example 3754-methyl-N-(3-(2-(trifluoromethyl)phenylthio)pyridin-2-yl)thiazol-2-amine

Step A: Preparation of 1,2-bis(2-(trifluoromethyl)phenyl)disulfane: Asolution of 2-(trifluoromethyl)benzenethiol (0.185 mL, 1.40 mmol) in wetacetonitrile (1:5 water/acetonitrile) was added Iodine (0.178 g, 0.702mmol) and allowed to stir over night at room temperature. The reactionwas concentrated, then diluted with EtOAc and quenched with aqueoussodium thiosulfate, extracted and dried organic with brine, Na₂SO₄,filtered and concentrated to afford the title compound (219 mg, 44%yield) as a colorless oil.

Step B: Preparation of4-methyl-N-(3-(2-(trifluoromethyl)phenylthio)pyridin-2-yl)thiazol-2-amine:A 25 mL round-bottomed flask was charged with3-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.082 g, 0.304 mmol)and THF (3 mL). The reaction was cooled to −78° C. and methyllithium(0.228 mL, 0.364 mmol) as a 1.6M solution in ether was added and stirredfor 5 minutes. Butyllithium (0.146 mL, 0.364 mmol) as a 2.5M solution inhexane was added and the reaction was stirred for 5 minutes.1,2-Bis(2-(trifluoromethyl)phenyl)disulfane (0.215 g, 0.607 mmol) wasadded and the reaction was warmed to room temperature and stirred forone hour. Saturated NH₄Cl was added, and the reaction mixture wasextracted with EtOAc. The combined organic layers were dried, filtered,and concentrated. The residue was purified on silica gel (1-10% EtOAc inhexanes) to afford the title compound (59 mg, 52% yield) as a whitesolid. ¹H NMR (CDCl₃) δ 9.04 (s, 1H), 8.47 (dd, 1H), 7.87 (dd, 1H), 7.69(m, 2H), 7.31 (m, 1H), 6.97 (q, 1H), 6.83 (d, 1H), 6.43 (m, 1H), 2.32(d, 3H). Mass spectrum (apci) m/z=368.2 (M+H).

The following compounds were prepared according to the method of Example375.

Example Structure Name Data 376

4-methyl-N-(3-(m- tolylthio)pyridin-2- yl)thiazol-2-amine hydrochloride¹H NMR (CDCl₃) δ 12.0 (bs, 1H), 8.36 (m, 1H), 7.91 (d, 1H), 7.31 (m,3H), 7.17 (t, 1H), 7.11 (m, 2H), 6.42 (s, 1H), 2.46 (m, 3H), 2.30 (s,3H). Mass spectrum (apci) m/z = 314.2 (M + H − HCl). 377

3-(2-(4-methylthiazol-2- ylamino)pyridin-3- ylthio)phenol Mass spectrum(apci) m/z = 316.2 (M + H). 378

N-(3-(2- fluorophenylthio)-5- (phenylthio)pyridin-2-yl)-4-methylthiazol-2- amine ¹H NMR (CDCl₃) δ 9.10 (bs, 1H), 8.45 (d,1H), 7.92 (d, 1H), 7.27 (m, 6H), 7.15 (m, 3H), 6.47 (m, 1H), 2.33 (m,3H). Mass spectrum (apci) m/z = 426.2 (M + H).

Example 379 Preparation ofN-(3-(2-bromo-5-morpholinophenoxy)pyridin-2-yl)-4-methylthiazol-2-amine

Step A: 4-(3-(2-Nitropyridin-3-yloxy)phenyl)morpholine. In a 125 mLround-bottom flask, 3-morpholinophenol (0.91 g, 5.07 mmol) was dissolvedin THF (40 mL). Solution was cooled to 0° C. and NaHMDS (5.07 mL, 5.07mmol) (1M in THF) was added slowly. The mixture was agitated for 15minutes and solution of 3-fluoro-2-nitropyridine (0.60 g, 4.22 mmol) inTHF (5 mL) was added slowly. After agitating for 2 hours the solvent wasevaporated and the residue dissolved in 100 mL of CH₂Cl₂ and washed withdiluted sodium bicarbonate solution twice, dried over magnesium sulfate,filtered and evaporated. Crude material was purified by chromatographyon silica gel, eluted with 25% ethyl acetate/Hexane to give the titlecompound (0.93 g, 72%) was obtained as thick red oil.

Step B: 3-(3-Morpholinophenoxy)pyridin-2-amine. In a 125 mL round-bottomflask, 4-(3-(2-nitropyridin-3-yloxy)phenyl)morpholine (0.92 g, 3.05mmol) was dissolved in 30 mL of ethanol and 200 mg of 10% Pd/C (Degussatype, 50% wet) added. The resulting mixture was agitated overnight underthe atmospheric pressure of hydrogen. The mixture was filtered and thesolvent was evaporated to give the title compound (0.80 g, 97%) as thickoil.

Step C: 3-(2-bromo-5-morpholinophenoxy)pyridin-2-amine. In a 250 mLround-bottom flask, 3-(3-morpholinophenoxy)pyridin-2-amine (0.720 g,2.654 mmol) was dissolved in 25 mL of acetic acid and Bromine (2.654 mL,2.654 mmol) (1M in AcOH) was added slowly. After agitating for 1 hourthe mixture was evaporated and the residue was distributed betweendichloromethane and sodium bicarbonate solution. The organic phase wasseparated and evaporated. The residue was purified by columnchromatography on silica gel, eluted with 1-3% methanol/dichloromethaneto give the title compound (0.72 g, 77%) as white solid.

Steps D, E and F:N-(3-(2-bromo-5-morpholinophenoxy)pyridin-2-yl)-4-methylthiazol-2-amine.Prepared according to the method of Example 7, Steps C, D and E; (0.48g, 61% yield). ¹H NMR (CDCl₃) δ 2.35 (s, 3H), 3.10 (t, 4H), 3.82 (t,4H), 6.42-6.89 (m, 5H), 7.48 (d, 1H), 8.07 (d, 1H), 8.71 (d, 1H).

Example 380 Preparation of methyl3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanoate

Step A: Preparation of methyl 4-bromo-2-methoxy-2-methylpent-4-enoate. A500 mL round-bottom flask was charged with diisopropylamine (12.89 mL,92.00 mmol) and dry THF (100 mL) and cooled to −78° C. Butyllithium (2.5M in hexanes) (36.80 mL, 92.00 mmol) was added dropwise over 20 minutesand the mixture was agitated for additional 30 minutes. Methyl2-methoxypropanoate (10.35 g, 87.61 mmol) was added dropwise over 20minutes and the mixture was agitated for 30 minutes. 2,3-Dibromopropene(10.70 mL, 87.61 mmol) was added dropwise over 20 minutes, the mixturewas agitated for 30 minutes and then allowed to warm up to ambienttemperature and agitated for additional 2 hours. The reaction wasquenched with saturated ammonium chloride solution and extracted twicewith ether. Extracts were washed with sodium bicarbonate solution,brine, dried and evaporated to give the title compound (22.7 g, 98.4%yield) as pale yellow oil.

Step B: Preparation of methyl5-bromo-2-methoxy-2-methyl-4-oxopentanoate. To a 125 mL round-bottomflask, methyl 4-bromo-2-methoxy-2-methylpent-4-enoate (0.525 g, 2.21mmol) was added acetonitrile (8 mL), water (2 mL) and N-bromosuccinimide(0.493 g, 2.77 mmol). A catalytic amount of 1M HBr was added (0.066 mL,0.066 mmol). The resulting solution was agitated overnight, diluted with50 mL of dichloromethane and washed twice with saturated sodiumbicarbonate, dried and evaporated. The residue was purified bychromatography on silica gel, eluting with 10% ethyl acetate/hexane toprovide the title compound (0.52 g, 92.8% yield) as clear oil.

Step C: Preparation of methyl3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanoate.In a 125 mL round-bottom flask,1-(5-bromo-3-phenoxypyridin-2-yl)thiourea (0.50 g, 1.54 mmol) (preparedas described in Example 10, Steps A-D) and methyl5-bromo-2-methoxy-2-methyl-4-oxopentanoate (0.586 g, 2.31 mmol) weredissolved in dry THF (25 mL), heated to 50° C. and agitated overnight.The solvent was evaporated and the residue was dissolved in chloroformand washed with diluted sodium bicarbonate solution twice, dried overmagnesium sulfate, filtered and evaporated. The resulting solid waspurified by chromatography on silica gel, eluted with 10-15% ethylacetate/hexane to give the title compound (0.485 g, 65.7% yield) asyellow solid. ¹H NMR (CDCl₃) δ 1.46 (s, 3H), 3.12 (s, 2H), 3.34 (s, 3H),3.73 (s, 3H), 6.58 (s, 1H), 7.06-7.45 (m, 6H), 8.11 (s, 1H), 8.64 (bs,1H).

Example 381 Preparation of3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanoicacid

Prepared according to the method of Example 45 from methyl3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanoate.¹H NMR (DMSO-d₆ δ 1.32 (s, 3H), 3.00 (q, 2H), 3.21 (s, 3H), 6.71 (s,1H), 7.11-7.23 (m, 3H), 7.36 (s, 1H), 7.44 (t, 2H), 8.12 (s, 1H).

Example 382 Preparation of3-(2-(5-brom-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methyl-1-(pyrrolidin-1-yl)propan-1-one

In a 20 mL scintillation vial,3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanoicacid (0.087 g, 0.187 mmol) was dissolved in CH₂Cl₂ (5 mL) and DMF (2 mL)and N-methylmorpholine (0.031 mL, 0.281 mmol), followed by addition of1-hydroxybenzotriazole. The mixture was cooled to 0° C. and EDCI (0.0467g, 0.244 mmol) was added. The resulting mixture was agitated for 30minutes and pyrrolidine (0.020 g, 0.28 mmol) was added. The mixture wasthen agitated overnight, diluted with 50 mL of CH₂Cl₂ and washed withcitric acid solution and sodium bicarbonate solution, dried andevaporated to give crude product which was purified by chromatography onsilica gel, eluting with 50-70% ethyl acetate/Hexane, to provide thetitle compound (0.079 g, 79% yield) as white solid. ¹H NMR (DMSO-d₆ δ1.23 (s, 3H), 1.66-1.80 (m, 4H), 3.03-3.63 (m, 9H), 7.01 (m, 1H),7.16-7.46 (m, 7H), 8.25 (s, 1H).

Example 383 Preparation of3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-N-(2-hydroxyethyl)-2-methoxy-2-methylpropanamide

Prepared according to the method of Example 382 from3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanoic.¹H NMR (DMSO-d₆ δ 1.40 (s, 3H), 3.14-3.48 (m, 9H), 7.03 (s, 1H),7.21-7.53 (m, 7H), 8.23 (s, 1H).

Example 384 Preparation ofN′-(3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanoyl)-N,N-dimethylformohydrazonamide

Step A: Preparation ofN′-acetyl-3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanehydrazide:In a 20 mL scintillation vial,3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanoicacid (0.087 g, 0.187 mmol) was dissolved in CH₂Cl₂ (5 mL) and DMF (2 mL)and N-methylmorpholine (0.0309 mL, 0.281 mmol), followed by addition ofHOBT. The mixture was cooled to 0° C. and EDCI (0.047 g, 0.244 mmol) wasadded. The resulting mixture was agitated for 30 minutes andacetohydrazide (0.021 g, 0.28 mmol) was added. The mixture was thenagitated overnight, diluted with 50 mL of CH₂Cl₂ and washed with citricacid solution, sodium bicarbonate solution twice, dried and evaporatedto give the title compound (0.0975 g, quantitative yield). Crude productwas used in the next step.

Step B: Preparation ofN′-(3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanoyl)-N,N-dimethylformohydrazonamide:In a 125 mL round-bottom flask,N′-acetyl-3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanehydrazide(0.0975 g, 0.187 mmol) was dissolved in 5 mL of acetonitrile andphosphorous oxychloride (0.052 mL, 0.56 mmol) was added. The resultingmixture was heated to 50° C. and agitated for two hours. The solvent wasevaporated and the residue was distributed between CH₂Cl₂ and saturatedsodium bicarbonate solution. The organic layer was washed with sodiumbicarbonate solution, dried and evaporated. The residue was purified bychromatography on silica gel, eluting with 20% ethyl acetate/hexane toafford the title compound (30 mg, 29%) as white solid. ¹H NMR (CDCl₃) δ1.50 (s, 3H), 2.86 (s, 6H), 3.16 (dd, 2H), 3.73 (s, 3H), 6.62 (s, 1H),7.06-7.45 (m, 6H), 7.71 (s, 1H), 8.11 (s, 1H), 8.58 (s, 1H), 8.71 (bs,1H).

Example 3853-(2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanoicacid

Step A: Preparation of methyl3-(2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanoate.Prepared according to the method of Example 380, Step C from1-(5-bromo-3-(phenylthio)pyridin-2-yl)thiourea.

Step B: Preparation of3-(2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanoicacid. Prepared according to the method of Example 381. ¹H NMR (DMSO-d₆ δ1.32 (s, 3H), 3.00 (q, 2H), 3.21 (s, 3H), 6.71 (s, 1H), 7.11-7.23 (m,3H), 7.36 (s, 1H), 7.44 (t, 2H), 8.12 (s, 1H). MS (APCI, pos) m/z 481(M+1).

Example 386 Preparation of3-(2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)-N-(2-hydroxyethyl)-2-methoxy-2-methylpropanamide

Prepared according to the method of Example 382 using 2-aminoethanol. ¹HNMR (DMSO-d₆ δ 1.40 (s, 3H), 3.14-3.48 (m, 9H), 7.03 (s, 1H), 7.21-7.53(m, 7H), 8.23 (s, 1H).

Example 3873-(2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)-2-methoxy-N-(2-methoxyethyl)-2-methylpropanamide

Prepared according to the method of Example 382 using2-methoxyethanamine. ¹H NMR (DMSO-d₆ δ 1.30 (s, 3H), 3.01-3.38 (m, 12H),7.03 (s, 1H), 7.21-7.53 (m, 7H), 8.23 (s, 1H).

Example 3883-(2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)-N-(2-hydroxyethyl)-2-methoxy-N,2-dimethylpropanamide

Prepared according to the method of Example 382 using2-(methylamino)ethanol. ¹H NMR (DMSO-d₆ δ 1.41 (s, 3H), 2.58 (t, 2H),3.13-3.28 (m, 8H), 4.20-4.35 (m, 2H), 7.03 (s, 1H), 7.21-7.53 (m, 7H),8.23 (s, 1H).

Example 3893-(2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)-1-((R)-3-hydroxypyrrolidin-1-yl)-2-methoxy-2-methylpropan-1-one

Prepared according to the method of Example 382 with(R)-pyrrolidin-3-ol. ¹H NMR (DMSO-d₆ δ 1.29 (s, 3H), 1.70-1.87 (m, 2H),3.03-3.48 (m, 7H), 4.25 (bd, 1H), 6.86 (bs, 1H), 7.36-7.50 (m, 5H), 7.79(bs, 1H), 8.47 (s, 1H).

Example 3901-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-ylmethyl)pyrrolidin-2-one

Step A: Preparation of 1-(3-chloro-2-hydroxypropyl)pyrrolidin-2-one.2-Pyrrolidinone (4.47 g, 52.5 mmol) was mixed with THF (25 mL) andcooled to −78° C. Butyllithium (1.6 M in hexanes) (32.8 mL, 52.5 mmol)was added slowly then and the mixture was agitated for 10 minutes. Borontrifluoride ethereate (6.59 mL, 52.5 mmol) was added dropwise, followedby dropwise addition of epichlorohydrin (4.11 mL, 52.5 mmol). Theresulting mixture was allowed to warm up overnight, then cooled andquenched with saturated sodium bicarbonate solution, and extracted 3times with ethyl acetate. The extracts were washed with brine, dried andevaporated to give ˜4 g of crude oil. The crude oil was purified bychromatography on silica gel, eluting with 1-2%methanol/dichloromethane, to provide the title compound (1.53 g, 16.4%yield) as clear oil.

Step B: Preparation of 1-(3-chloro-2-oxopropyl)pyrrolidin-2-one:1-(3-Chloro-2-hydroxypropyl)pyrrolidin-2-one (0.380 g, 2.14 mmol) wasdissolved in dichloromethane (10 mL) and cooled to 0° C. Dess-Martinperiodinane (0.907 g, 2.14 mmol) was added and the mixture agitated atambient temperature for 2 hours. The mixture was loaded on silica gelchromatographic column and eluted with 1% methanol/dichloromethane toprovide the title compound.

Step C: Preparation of1-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)pyrrolidin-2-one:Prepared according to the method of Example 7, Step E. ¹H NMR (DMSO-d₆ δ2.06-2.18 (m, 5H), 2.42 (t, 2H), 3.69 (t, 2H), 7.10 (d, 2H), 7.21 (t,1H), 7.42-7.47 (m, 3H), 8.21 (s, 1H).

Example 3913-((2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)methyl-1-methylpyrrolidin-2-one

Step A: 3-(2-bromoallyl)-1-methylpyrrolidin-2-one.1-Methyl-2-pyrrolidinone (3.87 mL, 40.3 mmol) was combined with 25 mL ofTHF and cooled to −78° C. Lithium diisopropylamide (26.9 mL, 40.3 mmol)(1.5M in THF) was added slowly and the mixture was agitated for 30minutes. 2,3-Dibromopropene (4.93 mL, 40.3 mmol) was added and themixture was agitated overnight and allowed to warm up to ambienttemperature. The reaction was quenched with sodium bicarbonate solutionand extracted twice with ether. The extracts were washed with brine andevaporated. The crude product was purified by chromatography on silicagel, eluting with 30-50% ethyl acetate/hexane, to provide the titlecompound (5.01 g, 56.9% yield) as clear oil.

Step B: 3-(3-bromo-2-oxopropyl)-1-methylpyrrolidin-2-one.3-(2-Bromoallyl)-1-methylpyrrolidin-2-one (1.40 g, 6.42 mmol) wasdissolved in acetonitrile (20 mL) and water (5 mL) andN-bromosuccinimide (1.71 g, 9.63 mmol) was added. The resulting mixturewas agitated for 4 hours, diluted with 200 mL of ether, washed withsodium bicarbonate, sodium thiosulfate, brine, dried and evaporated. Theresidue was purified by chromatography on silica gel, eluted with 1-2%methanol/dichloromethane to provide the title compound.

Step C:3-((2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)methyl)-1-methylpyrrolidin-2-one.Prepared according to the method of Example 7, step E. ¹H NMR (DMSO-d₆ δ1.60-1.72 (m, 1H), 2.08-2.14 (m, 1H), 2.51-2.58 (m, 1H), 2.68-2.78 (m,5H), 3.00 (d, 1H), 3.21-3.29 (m, 2H), 6.72 (s, 1H), 7.38-7.48 (m, 6H),8.41 (s, 1H).

Example 3923-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)-1-methylpyrrolidin-2-one

Prepared according to the method of Example 391, Step C, from1-(5-bromo-3-(phenoxypyridin-2-yl)thiourea and3-(3-bromo-2-oxopropyl)-1-methylpyrrolidin-2-one. ¹H NMR (DMSO-d₆ δ1.60-1.72 (m, 1H), 2.08-2.14 (m, 1H), 2.51-2.58 (m, 1H), 2.68-2.78 (m,5H), 3.02 (d, 1H), 3.21-3.29 (m, 2H), 6.80 (s, 1H), 7.13-7.47 (m, 6H),8.25 (s, 1H).

Example 3933-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)pyrrolidin-2-one

Step A: Preparation of tert-butyl3-(2-bromoallyl)-2-oxopyrrolidine-1-carboxylate. In a 250 mLround-bottom flask, tert-butyl 2-oxopyrrolidine-1-carboxylate (4.12 g,22.2 mmol) was combined with 25 mL of THF and cooled to −78° C. Lithiumdiisopropylamide (1.5M in THF) (14.8 mL, 22.2 mmol) was added slowly andthe mixture was agitated for 30 minutes. 2,3-Dibromopropene (2.72 mL,22.2 mmol) was added and the mixture was agitated overnight and allowedto warm to ambient temperature. The reaction was then quenched withsodium bicarbonate solution and extracted twice with ether. The extractswere washed with brine and evaporated. The crude product was purified bycolumn chromatography, eluting with 20% ethyl acetate/hexane, to providethe title compound (0.560 g, 8.3% yield).

Step B: Preparation of tert-butyl3-(3-bromo-2-oxopropyl)-2-oxopyrrolidine-1-carboxylate. In a 125 mLround-bottom flask, tert-butyl3-(2-bromoallyl)-2-oxopyrrolidine-1-carboxylate (0.560 g, 1.84 mmol) wasdissolved in mixture of acetonitrile (8 mL) and water (2 mL).N-bromosuccinimide (0.41 g, 2.30 mmol) was added and the mixture wasagitated overnight. The reaction mixture was diluted with 100 mL ofether, washed with sodium bicarbonate solution, brine, dried andevaporated to provide the title compound (0.25 g, 42.4% yield).

Step C: Preparation of3-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)-1-methylpyrrolidin-2-one.Prepared according to the method of Example 7, step E.

Step D: Preparation of3-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)pyrrolidin-2-one.In a 20 mL scintillation vial, tert-butyl3-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)-2-oxopyrrolidine-1-carboxylate(35 mg, 0.064 mmol) was dissolved in CH₂Cl₂ (1 mL) and HCl (4.0Msolution in dioxane) (2.00 mL, 8.00 mmol) was added. The resultingmixture was agitated overnight. The solvents and excess HCl wereevaporated, and product was obtained as yellow solid (25 mg, 87.5%yield). ¹H NMR (DMSO-d₆ δ 1.70-1.80 (m, 1H), 2.12-2.20 (m, 1H),2.60-2.74 (m, 1H), 3.02 (d, 1H), 3.16-3.22 (m, 2H), 3.44-3.76 (m, 5H),6.97 (s, 1H), 7.19-7.50 (m, 6H), 7.83 (s, 1H), 8.30 (s, 1H).

Example 3943-((2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)methyl)pyrrolidin-2-one

Prepared according to the method of Examples 391 and 393. ¹H NMR((CD₃)₂SO) δ 1.70-1.80 (m, 1H), 2.12-2.20 (m, 1H), 2.60-2.74 (m, 1H),3.02 (d, 1H), 3.16-3.22 (m, 2H), 3.44-3.76 (m, 5H), 6.77 (s, 1H),7.38-7.50 (m, 6H), 7.76 (s, 1H), 8.43 (s, 1H).

Example 3952-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)-4-(tert-butoxycarbonylamino)butanoicacid

tert-Butyl3-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)-2-oxopyrrolidine-1-carboxylate(0.070 g, 0.128 mmol) (Example 393, Steps A-C) was dissolved in 1 mL ofTHF and sodium hydroxide (0.963 mL, 1.93 mmol) 2M solution was added.The resulting solution was heated to 55° C. and agitated for 3 hours.Reaction was quenched with 3 mL of 2M potassium hydrosulfate solutionand extracted twice with ethyl acetate. The extracts were washed withwater, brine, dried and evaporated to produce the title compound. ¹H NMR(CDCl₃) δ 1.40 (s, 9H), 1.60-1.74 (m, 2H), 2.64-3.08 (m, 5H), 4.65 (bs,1H), 6.47 (s, 1H), 7.09-7.43 (m, 7H), 8.14 (s, 1H).

Example 3962-((2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)methyl)-4-(tert-butoxycarbonylamino)butanoicacid

Prepared according to the method of Example 395 from tert-butyl3-((2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)methyl)-2-oxopyrrolidine-1-carboxylate.¹H NMR (CDCl₃) δ 1.41 (s, 9H), 1.64-1.86 (m, 2H), 2.80-3.22 (m, 5H),4.93 (bs, 1H), 6.55 (s, 1H), 7.22-7.32 (m, 6H), 7.85 (s, 1H), 8.38 (s,1H).

Example 3974-amino-2-((2-(5-brom-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)butanoic acid

Prepared according to the method of Example 393, Step D. ¹H NMR (DMSO-d₆δ 1.65-1.79 (m, 21H), 2.74-3.10 (m, 5H), 6.55 (s, 1H), 7.12-7.45 (m,7H), 8.26 (s, 1H).

Example 3981-(4-(2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone

Step A: Preparation of1-acetyl-N-methoxy-N-methylpiperidine-4-carboxamide. To a solution of1-acetylpiperidine-4-carboxylic acid (58.50 g, 342 mmol) indichloromethane (700 mL) was added di(1H-imidazol-1-yl)methanone (58.18g, 359 mmol). After the addition the mixture was agitated for two hoursand N-methoxymethanamine hydrochloride (35.00 g, 359 mmol) was added atonce. The mixture was allowed to agitate overnight at ambienttemperature and 4M HCl in dioxane (75 mL) was added slowly. The slurrywas agitated for 30 minutes and then filtered. Filtrate was washed twicewith sodium bicarbonate solution, dried and concentrated to give thetitle compound (59.10 g, 80.72% yield).

Step B: Preparation of 1,1′-(piperidine-1,4-diyl)diethanone.1-Acetyl-N-methoxy-N-methylpiperidine-4-carboxamide (59.10 g, 276 mmol)was dissolved in THF (800 mL) and cooled to 0° C. Methylmagnesiumbromide (110.3 mL, 331 mmol) (3.0M in diethyl ether) was added slowlyand the resulting white slurry was agitated for 1 hour. The reaction wasquenched with 300 mL of 2M HCl and the solvent was evaporated. Theresulting aqueous slurry was filtered and the solids were washed withwater and small amount of ether to provide the title compound (38.4 g,82.2% yield).

Step C: Preparation of 1-(1-acetylpiperidin-4-yl)-2-bromoethanone.1,1′-(Piperidine-1,4-diyl)diethanone (38.0 g, 225 mmol) was dissolved inmethanol (700 mL) and bromine (12.1 mL, 236 mmol) was added. Afteragitating for 3 hours the solvent was removed. The resulting solid waswashed with ethyl acetate, then distributed between ethyl acetate andsodium carbonate. The organic phase was separated, washed with brine,dried and evaporated to give the title compound.

Step D: Preparation of1-(4-(2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone.Prepared according to the method of Example 7, Step E ¹H NMR (CDCl₃) δ1.58-1.64 (m, 2H), 1.99-2.11 (m, 5H), 2.64-2.86 (m, 2H), 3.16 (t, 1H),3.88 (d, 1H), 4.68 (d, 1H), 6.44 (s, 1H), 7.18-7.32 (m, 5H), 7.92 (s,1H), 8.23 (s, 1H), 8.50 (s, 1H).

Example 3992-(dimethylamino)-1-(4-(5-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanonetrihydrochloride

Prepared according to the method of Example 198. ¹H NMR (d₆-DMSO) δ12.49 (bs, 1H), 9.62 (bs, 1H), 8.58 (d, 1H), 8.52 (d, 1H), 8.33 (d, 1H),7.69 (d, 1H), 7.59 (d, 1H), 7.23 (m, 4H), 7.08 (d, 1H), 4.41-4.22 (m,3H), 3.66 (d, 1H), 3.28-3.11 (m, 2H), 3.01-2.89 (m, 2H), 2.82 (d, 6H),2.09 (m, 2H), 1.82 (m, 1H), 1.65 (m, 1H). Mass spectrum (apci) m/z=622.2(M+H-3HCl).

Example 4001-(4-((5-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)methyl)piperidin-1-yl)ethanonedihydrochloride

Step A: Preparation of tert-butyl4-((5-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)methyl)piperidine-1-carboxylate:Prepared according to the method of Example 127 from tert-butyl4-((5-(3-(4-fluorophenoxy)-5-(3-methoxy-3-oxopropylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)methyl)piperidine-1-carboxylate(Example 96, 230 mg, 0.381 mmol).

Step B: Preparation of3-(4-fluorophenoxy)-N-(3-(piperidin-4-ylmethyl)-1,2,4-thiadiazol-5-yl)-5-(thieno[3,2-b]pyridin-2-aminetrihydrochloride: A 10 mL round-bottomed flask was charged withtert-butyl4-((5-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)methyl)piperidine-1-carboxylate(52.2 mg, 0.0802 mmol) and a 1:1 mix of methanol and CH₂Cl₂ (4 mL). 4NHCl in dioxane (2 mL) was added and the reaction stirred at roomtemperature for 10 minutes. The solvent was removed to afford crude3-(4-fluorophenoxy)-N-(3-(piperidin-4-ylmethyl)-1,2,4-thiadiazol-5-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-aminetrihydrochloride (52.9 mg, 100%).

Step C: Preparation of1-(4-((5-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)methyl)piperidin-1-yl)ethanonedihydrochloride: Prepared according to the method of Example 198. ¹H NMR(d₆-DMSO) δ 12.46 (bs, 1H), 8.58 (d, 1H), 8.52 (d, 1H), 8.33 (d, 1H),7.68 (d, 1H), 7.57 (d, 1H), 7.23 (m, 4H), 7.08 (d, 1H), 4.34 (d, 1H),3.78 (d, 1H), 2.99 (t, 1H), 2.72 (d, 2H), 2.09 (m, 1H), 1.97 (s, 3H),1.65 (m, 2H), 1.18 (m, 1H), 1.05 (m, 1H). Mass spectrum (apci) m/z=593.2(M+H-2HCl).

Example 4011-(4-(5-(3-(4-fluorophenoxy)-5-(3-methylisoxazolo[5,4-b]pyridin-4-ylthiopyridin-2-amino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanonehydrochloride

Prepared according to Example 400, using tert-butyl4-(5-(3-(4-fluorophenoxy)-5-(3-methylisoxazolo[5,4-b]pyridin-4-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylatein Step B. ¹H NMR (d₆-DMSO) δ 12.48 (bs, 1H), 8.49 (d, 1H), 8.32 (d,1H), 7.54 (m, 1H), 7.25 (m, 4H), 6.75 (d, 1H), 4.33 (d, 1H), 3.85 (d,1H), 3.20 (m, 1H), 3.07 (m, 1H), 2.77 (t, 1H), 2.69 (s, 3H), 2.02 (m,5H), 1.74 (m, 1H), 1.60 (m, 1H). Mass spectrum (apci) m/z=578.1(M+H—HCl).

Example 4022-(dimethylamino)-1-(4-(5-(3-(4-fluorophenoxy)-5-(3-methylisoxazolo[5,4-b]pyridin-4-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanonedihydrochloride

Prepared according to the method of Example 198 using3-(4-fluorophenoxy)-5-(3-methylisoxazolo[5,4-b]pyridin-4-ylthio)-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)pyridin-2-amine.¹H NMR (d₆-DMSO) δ 12.44 (bs, 1H), 9.55 (bs, 1H), 8.49 (d, 1H), 8.32 (d,1H), 7.55 (d, 1H), 7.25 (m, 4H), 6.74 (d, 1H), 4.32 (m, 3H), 3.65 (d,1H), 3.28-3.10 (m, 2H), 2.97 (t, 1H), 2.82 (d, 6H), 2.70 (s, 3H), 2.10(d, 2H), 1.82 (m, 1H), 1.66 (m, 1H). Mass spectrum (apci) m/z=621.1(M+H-2HCl).

Example 4035-(3-bromophenoxy)-3-(3-methoxyphenylthio)-N-(3-(tetrahydrofuran-2-yl)-1,2,4-thiadiazol-5-yl)pyridin-2-aminehydrochloride

Step A: Preparation of 5-bromo-3-(3-methoxyphenylthio)picolinonitrile: A10 mL round-bottomed flask was charged with5-bromo-3-nitropicolinonitrile (300 mg, 1.31 mmol),3-methoxybenzenethiol (0.150 mL, 1.31 mmol), and DMF (12 mL). NaH (37.8mg, 1.58 mmol) was added and reaction stirred at room temperature for 10minutes. The reaction was poured into water and extracted with EtOAc.The organic layer was dried over sodium sulfate, filtered andconcentrated. The resulting residue was purified on silica gel (10%EtOAc in Hexanes) to afford the title compound (345 mg, 81%).

Step B: Preparation of 5-(3-bromophenoxy)-3-(3-methoxyphenylthio)picolinonitrile: A 10 mL round-bottomed flask was charged with5-bromo-3-(3-methoxyphenylthio)picolinonitrile (214 mg, 0.666 mmol),3-bromophenol (138 mg, 0.800 mmol), and DMF (6 mL). NaH (24.0 mg, 0.999mmol) was added and reaction stirred at room temperature for 24 hours.The reaction was poured into water and extracted with EtOAc. The organiclayer was dried over sodium sulfate, filtered and concentrated. Theresulting residue was purified on silica gel (10% EtOAc in Hexanes) toafford the title compound (225 mg, 81.7% yield).

Step C: Preparation of5-(3-bromophenoxy)-3-(3-methoxyphenylthio)picolinic acid: A 25 mLround-bottomed flask was charged with5-(3-bromophenoxy)-3-(3-methoxyphenylthio)picolinonitrile (225 mg, 0.544mmol), potassium hydroxide (2.5 M, 1.09 mL, 2.72 mmol), and EtOH (5 mL).The reaction was heated to reflux overnight. After cooling to roomtemperature the reaction was poured into water and pH adjusted with 1NHCl to ˜pH=3. The cloudy solution was extracted with CH₂Cl₂. The organiclayer was dried over sodium sulfate, filtered and concentrated to affordthe title compound (235 mg, 100%) which was taken forward withoutfurther purification.

Step D: Preparation of5-(3-bromophenoxy)-3-(3-methoxyphenylthio)pyridin-2-amine: A 25 mLround-bottomed flask was charged with 2-methylpropan-2-ol (0.284 mL,3.26 mmol), 5-(3-bromophenoxy)-3-(3-methoxyphenylthio)picolinic acid(235 mg, 0.544 mmol), triethylamine (0.0985 mL, 0.707 mmol), and Toluene(5 mL). The reaction was heated to 100° C. and DPPA (0.118 mL, 0.544mmol) was added dropwise. The reaction was stirred at 100° C. forminutes after complete addition and then cooled to room temperature andpartitioned between CH₂Cl₂ and water. The organic layer was dried oversodium sulfate, filtered and concentrated. The residue was purified onsilica gel (10% EtOAc in hexanes) to afford the Boc protected material.This residue was dissolved in 1:1CH₂Cl₂:methanol (4 mL) and 4N HCl indioxane (2 mL) was added and stirred at room temperature for 4 hours.The solvent was removed and partitioned between aqueous sodiumbicarbonate and CH₂Cl₂. The organic phase was dried, filtered andconcentrated to afford the title compound (128 mg, 58.4% yield).

Step E: Preparation of5-(3-bromophenoxy)-3-(3-methoxyphenylthio)-N-(3-(tetrahydrofuran-2-yl)-1,2,4-thiadiazol-5-yl)pyridin-2-amine:Prepared according to the method of Example 183 step D.

Step F: Preparation of5-(3-bromophenoxy)-3-(3-methoxyphenylthio)-N-(3-(tetrahydrofuran-2-yl)-1,2,4-thiadiazol-5-yl)pyridin-2-aminehydrochloride: A 10 mL round-bottom flask was charged with5-(3-bromophenoxy)-3-(3-methoxyphenylthio)-N-(3-(tetrahydrofuran-2-yl)-1,2,4-thiadiazol-5-yl)pyridin-2-amine(20 mg, 0.036 mmol) and dissolved in CH₂Cl₂ (1 mL). 2M HCl in ether (0.1mL, 0.2 mmol) was added and the solvent removed to afford the titlecompound (21 mg, 100%). ¹H NMR (d₆-DMSO) δ 11.51 (bs, 1H), 8.40 (d, 1H),8.36 (bs, 1H), 7.68 (bs, 1H), 7.51-7.18 (m, 5H), 7.10-6.73 (m, 3H),4.10-3.74 (m, 3H), 3.72 (s, 3H), 2.25 (m, 4H). Mass spectrum (apci)m/z=559.1 (M+H—HCl).

Example 4043-(3-methoxyphenylthio)-5-phenoxy-N-(3-(tetrahydrofuran-2-yl)-1,2,4-thiadiazol-5-yl)pyridin-2-aminehydrochloride

A 10 mL round-bottomed flask was charged with5-(3-bromophenoxy)-3-(3-methoxyphenylthio)-N-(3-(tetrahydrofuran-2-yl)-1,2,4-thiadiazol-5-yl)pyridin-2-amine(41 mg, 0.074 mmol) and THF (2 mL). The reaction was cooled to −78° C.and methyllithium (0.055 mL, 0.088 mmol) was added and stirred for 5minutes. Butyllithium (0.035 mL, 0.088 mmol) was added and stirred for 5minutes. The reaction was then poured into saturated aqueous NH₄Cl andextract with EtOAc. The organic layer was dried with sodium sulfate,filtered and concentrated. The residue was purified on silica gel (35%ethyl acetate in hexanes) to afford the title compound (36 mg, 95%)after HC salt formation. ¹H NMR (d₆-DMSO) δ 11.47 (bs, 1H), 8.30 (bs, 1h), 7.59 (bs, 1H), 7.37 (m, 2H), 7.28 (t, 1H), 7.14 (t, 1H), 7.03 (d,2H), 6.88 (m, 3H), 4.04 (t, 1H), 3.90-3.75 (m, 3H), 3.72 (s, 3H), 3.57(m, 1H), 2.25 (m, 2H). Mass spectrum (apci) m/z=479.2 (M+H—HCl).

Example 4051-(3-(5-(3-methoxyphenylthio)-6-(3-(tetrahydrofuran-2-yl)-1,2,4-thiadiazol-5-ylamino)pyridin-3-yloxy)phenyl)ethanol

A 10 mL round-bottomed flask was charged with5-(3-bromophenoxy)-3-(3-methoxyphenylthio)-N-(3-(tetrahydrofuran-2-yl)-1,2,4-thiadiazol-5-yl)pyridin-2-amine(43.3 mg, 0.077 mmol) and THF (2 mL). The reaction was cooled to −78° C.and methyllithium (0.058 mL, 0.093 mmol) was added and stirred for 5min. Butyllithium (0.037 mL, 0.093 mmol) was added and the reaction wasstirred for 5 min. Acetaldehyde (0.0086 mL, 0.16 mmol) was added and thereaction warmed to room temperature and poured into saturated aqueousNH₄Cl and extracted with EtOAc. The organic layer was dried with sodiumsulfate, filtered and concentrated. The residue was purified on silicagel (35 to 100% ethyl acetate in hexanes) to afford the title compound(4.5 mg, 11.1% yield). ¹H NMR (CDCl₃) δ 9.26 (bs, 1H), 8.25 (d, 1H),7.63 (d, 1H), 7.33 (t, 1H), 7.21 (t, 1H), 7.14 (d, 1H), 7.05 (m, 1H),6.90 (dd, 1H), 6.76 (m, 2H), 6.70 (m, 1H), 4.89 (q, 1H), 4.15 (t, 1H),4.03 (m, 2H), 3:90 (m, 1H), 3.77 (s, 3H), 3.64 (m, 1H), 2.34 (q, 2H),1.47 (d, 3H). Mass spectrum (apci) m/z=523.2 (M+H).

Example 4063-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)-N-(4-(piperidin-4-yl)thiazol-2-yl)pyridin-2-amine

Steps A-E: Preparation of1-benzoyl-3-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-yl)thiourea:Prepared according to Example 403, Steps A-D.

Step F: A 250 mL round-bottomed flask was charged with3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-amine (7.4g, 17.6 mmol), benzoyl isothiocyanate (3.08 mL, 22.8 mmol), and THF (125mL). The reaction was stirred at room temperature overnight. Hexanes(700 mL) was added and stirred at room temperature for 1 hour. The solidmaterial was decanted to afford 5.6 g of material as a yellow foam. Themother liquor was concentrated and resuspended in 9:1 hexanes:EtOAc (200mL) to afford another 4.7 g of material. The combined crops afforded thetitle compound (10.3 g, 100%).

Step G: Preparation of1-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-yl)thiourea: A 250 mL round-bottomed flask was charged with1-benzoyl-3-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-yl)thiourea(10.3 g, 17.6 mmol) and EtOH (125 mL). 3M Sodium hydroxide (11.7 mL,35.2 mmol) was added and heated to 50° C. overnight. The reaction wascooled to room temperature and poured into 750 mL water and stirredvigorously for 1 hour. The solids were filtered to afford the titlecompound (6.5 g, 76.8% yield).

Step H: Preparation of tert-butyl4-(2-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate:A 50 mL round-bottomed flask was charged with1-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-yl)thiourea(1.5 g, 3.12 mmol), triethylamine (0.740 mL, 5.31 mmol), tert-butyl4-(2-bromoacetyl)piperidine-1-carboxylate (1.15 g, 3.75 mmol), and EtOH(25 mL). The reaction was heated to 70° C. for 3 hours. The reaction wascooled to room temperature and partitioned between EtOAc and water. Theorganic layer was dried over sodium sulfate, filtered and concentrated.The residue was purified on silica gel (10% EtOAc in hexanes) to afford(1.76 g, 82.0% yield).

Step I: Preparation of3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)-N-(4-(piperidin-4-yl)thiazol-2-yl)pyridin-2-amine:A 20 mL vial was charged with tert-butyl4-(2-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate(100 mg, 0.145 mmol) and CH₂Cl₂ (2 mL). TFA (2 mL) was added and stirredat room temperature for 5 minutes. The reaction was poured into waterand diluted with CH₂Cl₂. Solid Na₂CO₃ added slowly to neutralize theTFA. The aqueous layer was extracted and dried to afford the titlecompound (88 mg, 103% yield). ¹H NMR (d₆-DMSO) δ 8.16 (d, 1H), 7.74 (m,1H), 7.30 (m, 2H), 7.21 (t, 1H), 6.92 (d, 1H), 6.78 (m, 1H), 6.70 (m,3H), 3.69 (s, 3H), 3.17 (m, 2H), 2.77 (m, 3H), 2.01 (m, 2H), 1.62 (m,2H). Mass spectrum (apci) m/z=587.2, 589.2 (M+H).

Example 4074-(2-(3-(4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylatetrifluoroacetate

A 10 mL round-bottomed flask was charged with tert-butyl4-(2-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate(200 mg, 0.29 mmol) and THF (3 mL). The reaction was cooled to −78° C.and methyllithium (0.22 mL, 0.35 mmol) was added and stirred for 5 min.Butyllithium (0.140 mL, 0.35 mmol) was added and the reaction wasstirred for 5 min. Iodomethane (0.0273 mL, 0.436 mmol) was added and thereaction was stirred for 5 min and then poured into saturated aqueousNH₄Cl and extracted with EtOAc (1×20 mL). The organic layer was driedwith sodium sulfate, filtered and concentrated to afford a mixture ofproducts. The residue was purified on reverse phase column (35 to 100%acetonitrile in water with 0.1% TFA) to afford the title compound (68.3mg, 33% yield). ¹H NMR (CDCl₃) δ 8.13 (d, 1H), 7.28 (d, 1H), 7.22 (m,1H), 7.04 (m, 4H), 6.85 (m, 1H), 6.80 (m, 2H), 6.43 (s, 1H), 4.22 (m,2H), 3.76 (s, 3h), 2.89 (m, 3H), 2.06 (m, 2H), 1.56 (m, 2H), 1.47 (s,9H).

Example 4081-(4-(2-(3-(4-fluoro-2-methylphenoxy)-5-(3-methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanonehydrochloride

Step A: Preparation of tert-butyl4-(2-(3-(4-fluoro-2-methylphenoxy)-5-(3-methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylatetrifluoroacetate: From the reaction mixture in Example 407, the titlecompound was isolated from the reverse phase chromatography (70 mg, 33%yield).

Step B: Preparation ofN-(3-(4-fluoro-2-methylphenoxy)-5-(3-methoxyphenylthio)pyridin-2-yl)-4-(piperidin-4-yl)thiazol-2-amineditrifluoroacetate: A 10 mL round-bottomed flask was charged withtert-butyl4-(2-(3-(4-fluoro-2-methylphenoxy)-5-(3-methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylatetrifluoroacetate (70 mg, 0.097 mmol) and CH₂Cl₂ (2 mL). TFA (2 mL) wasadded and stirred at room temperature for minutes. The solvent wasremoved and dried on high vacuum overnight. The crude material was takenon to the next reaction without further purification.

Step C: Preparation of1-(4-(2-(3-(4-fluoro-2-methylphenoxy-5-(3-methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanonehydrochloride: A 20 mL vial was charged with3-(4-fluoro-2-methylphenoxy)-5-(3-methoxyphenylthio)-N-(4-(piperidin-4-yl)thiazol-2-yl)pyridin-2-amineditrifluoroacetate (70 mg, 0.098 mmol) and CH₂Cl₂ (2 mL). Triethylamine(0.109 mL, 0.78 mmol) was added followed by Ac₂O (0.012 mL, 0.12 mmol)and the reaction was stirred for 5 minutes. The reaction was poured intosaturated aqueous NaHCO₃ and extracted with CH₂Cl₂ (1×20 mL). Theorganic layer was dried with sodium sulfate, filtered and concentrated.The residue was purified on silica gel (20 to 40% EtOAc in hexanes) toafford the title compound (44.8 mg, 76.3% yield) after HCl saltformation. ¹H NMR (d₆-DMSO) δ 11.20 (bs, 1H), 8.14 (d, 1H), 7.22 (m,2H), 7.04 (m, 2H), 6.88 (d, 1H), 6.77 (m, 2H), 6.71 (m, 2H), 4.43 (d,1H), 3.88 (d, 1H), 3.69 (s, 3H), 3.14 (t, 1H), 2.87 (m, 1H), 2.65 (m,1H), 2.19 (s, 3H), 2.01 (s, 3H), 1.95 (m, 2H), 1.58 (m, 1H), 1.45 (m,1H). Mass spectrum (apci) m/z=565.3 (M+H—HCl).

Example 4091-(4-(2-(3-(4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanonehydrochloride

Step A: Preparation of3-(4-fluorophenoxy)-5-(3-methoxyphenylthio)-N-(4-(piperidin-4-yl)thiazol-2-yl)pyridin-2-amineditrifluoroacetate: A 10 mL round-bottomed flask was charged withtert-butyl4-(2-(3-(4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-ylamino)thiazol-4-1)piperidine-1-carboxylate(68 mg, 0.11 mmol) and CH₂Cl₂ (2 mL). TFA (2 mL) was added and stirredat room temperature for 30 minutes. The reaction was concentrated andtaken on to next reaction without further purification.

Step B: Preparation of1-(4-(2-(3-(4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanonehydrochloride: Prepared according to the method of Example 198. ¹H NMR(d₆-DMSO) δ 11.10 (bs, 1H), 8.19 (m, 1H), 7.22 (m, 4H), 7.15 (m, 2H),6.79 (m, 1H), 6.74 (m, 3H), 4.42 (d, 1H), 3.87 (d, 1H), 3.70 (s, 3H),3.13 (t, 1H), 2.85 (t, 1H), 2.63 (t, 1H), 2.01 (d, 3H), 1.94 (m, 2H),1.57 (m, 1H), 1.44 (m, 1H). Mass spectrum (esi) m/z=551.0 (M+H—HCl).

Example 4101-(4-(2-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanonehydrochloride

A 20 mL vial was charged with3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)-N-(4-(piperidin-4-yl)thiazol-2-yl)pyridin-2-amine(40 mg, 0.068 mmol), triethylamine (0.0190 mL, 0.14 mmol), and CH₂Cl₂ (2mL). Ac₂O (0.008 mL, 0.082 mmol) was added and the reaction was stirredat room temperature for 10 minutes. The reaction was partitioned betweenCH₂Cl₂ and saturated aqueous sodium bicarbonate. The organic layer wasdried with sodium sulfate, filtered and concentrated to afford the titlecompound (38.2 mg, 84.2% yield) as a white solid after HCl saltformation. ¹H NMR (d₆-DMSO) δ 11.20 (bs, 1H), 8.17 (d, 1H), 7.74 (m,1H), 7.31 (m, 2H), 7.21 (t, 1H), 6.93 (d, 1H), 6.78 (m, 1H), 6.74 (s,1H), 6.71 (m, 2H), 4.43 (d, 1H), 3.87 (d, 1H), 3.69 (s, 3H), 3.14 (m,1H), 2.86 (m, 1H), 2.64 (m, 1H), 2.01 (s, 3H), 1.95 (m, 2H), 1.58 (m,1H), 1.45 (m, 1H). Mass spectrum (apci) m/z=631.4 (M+H—HCl).

Example 4111-(4-(2-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)-2-(dimethylamino)ethanonedihydrochloride

A 20 mL vial was charged with3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)-N-(4-(piperidin-4-yl)thiazol-2-yl)pyridin-2-amine(40 mg, 0.068 mmol), triethylamine (0.028 mL, 0.20 mmol), and CH₂Cl₂ (2mL). 2-(Dimethylamino)acetyl chloride hydrochloride (12.9 mg, 0.0817mmol) was added and stirred at room temperature for 10 minutes. Thereaction was partitioned between CH₂Cl₂ and saturated aqueous sodiumbicarbonate. The organic layer was dried with sodium sulfate, filteredand concentrated. The residue was purified on silica gel (15% MeOH inEtOAc with 0.3% ammonia) to afford the title compound (35.6 mg, 70.1%yield) after HCl salt formation. ¹H NMR (d₆-DMSO) δ 11.15 (bs, 1H), 9.60(bs, 1H), 8.17 (d, 1H), 7.75 (m, 1H), 7.32 (m, 2H), 7.21 (t, 1H), 6.94(d, 1H), 6.79 (m, 1H), 6.75 (s, 1H), 6.71 (m, 2H), 4.42 (d, 1H), 4.31(qd, 2H), 3.69 (s, 3H), 3.19 (t, 1H), 2.93 (m, 1H), 2.82 (m, 6H), 2.04(d, 2H), 1.64 (m, 1H), 1.52 (m, 1H). Mass spectrum (apci) m/z=674.3(M+H-2HCl).

The following compounds were prepared by the method of Example 127.

Ex- ample Structure Name NMR Data 412

1-(4-(2-(5- (Thieno[3,2- b]pyridin-7- ylthio)-3-(4- (trifluoromethyl)phenoxy)pyridin- 2-ylamino) thiazol-4-yl) piperidin-1- yl)ethanone H¹NMR (d₆ DMSO) δ 1.23-1.47 (m, 1H), 1.52-1.60 (m, 1H), 1.93 (t, J = 15.5Hz, 2H), 2.00 (s, 3H), 2.62 (t, J = 12.4 Hz, 1H), 2.83 (br s, 1H), 3.12(t, J = 12.1 Hz, 1H), 3.85 (d, J = 13.1 Hz, 1H), 4.42 (d, J = 13.3 Hz,1H), 6.76 (s, 1H), 6.95 (d, J = 5.1 Hz, 1H), 7.23 (d, J = 6.4 Hz, 2H),7.59 (d, J = 5.5 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.79 (s, 1H), 8.16(d, J = 5.5 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 4.9 Hz, 1H),11.44 (s, 1H). 413

1-(4-(2-(5- (Thieno[3,2- b]pyridin-7- ylthio)-3-(2- (trifluoromethyl)phenoxy)pyridin- 2-ylamino) thiazol-4-yl) piperidin-1- yl)ethanone H¹NMR (d₆ DMSO) δ 1.40-1.49 (m, 1H), 1.54-1.62 (m, 1H), 1.91- 2.00 (m,5H), 2.63 (t, J = 12.3 Hz, 1H), 2.85 (br s, 1H), 3.13 (t, J = 12.3 Hz,1H), 3.87 (d, J = 13.8 Hz, 1H), 4.43 (d, J = 13.1 Hz, 1H), 6.76 (br s,1H), 6.88 (d, J = 5.1 Hz, 1H), 7.21 (br s, 1H), 7.32-7.36 (m, 2H), 7.58(d, J = 5.5 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H),8.16 (d, J = 5.5 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.48 (d, J = 5.1 Hz,1H), 11.35 (br s, 1H). 414

1-(4-(2-(5-(2- Methylthieno [3,2-b]pyridin-7- ylthio)-3- phenoxy-pyridin-2- ylamino)thiazol- 4-yl)piperidin-1- yl)ethanone H¹ NMR (CDCl₃)δ 1.59-1.70 (m, 2H), 2.04-2.12 (m, 5H), 2.63 (d, J = 1.2 Hz, 3H), 2.70(t, J = 11.5 Hz, 1H), 2.84-2.90 (m, 1H), 3.19 (t, J = 11.7 Hz, 1H), 3.91(d, J = 13.9 Hz, 1H), 4.72 (d, 3 = 13.3 Hz, 1H), 6.51 (s, 1H), 6.66 (d,J = 5.3 Hz, 1H), 7.04 (s, 1H), 7.06 (d, 3 = 1.0 Hz, 1H), 7.17-7.23 (m,3H), 7.39 (t, J = 7.9 Hz, 2H), 8.29 (d, J = 2.0 Hz, 1H), 8.37 (d, J =5.1 Hz, 1H), 8.84 (brs, 1H). 415

1-(4-(2-(5-(4- Methoxy- pyrimidin- 2-ylthio)-3- phenoxypyridin-2-ylamino) thiazol-4- yl)piperidin-1- yl)ethanone H¹ NMR (CDCl₃) δ1.59-1.70 (m, 2H), 2.03-2.12 (m, 5H), 2.69 (t, J = 11.6 Hz, 1H),2.83-2.89 (m, 1H), 3.14-3.22 (m, 1H), 3.76 (s, 3H), 3.90 (d, J = 13.5Hz, 1H), 4.71 (d, J = 13.2 Hz, 1H), 6.39 (d, J = 5.7 Hz, 1H), 6.48 (s,1H), 7.08 (s, 1H), 7.10 (s, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.32 (d, J =1.8 Hz, 1H), 7.39 (t, J = 8.0 Hz, 2H), 8.15 (d, J = 5.9 Hz, 1H), 8.27(d, J = 1.8 Hz, 1H), 8.77 (br s, 1H). 416

4-(6-(4-(1- Acetylpiperidin- 4-yl)thiazol-2- ylamino)-5- phenoxypyridin-3-ylthio) benzonitrile H¹ NMR (CDCl₃) δ 1.59-1.71 (m, 2H), 1.96-2.12 (m,5H), 2.70 (t, J = 11.5 Hz, 1H), 2.84-2.90 (m, 1H), 3.15-3.22 (m, 1H),3.91 (d, J = 13.5 Hz, 1H), 4.72 (d, J = 13.3 Hz, 1H), 6.51 (s, 1H), 7.05(s, 1H), 7.07 (s, 1H), 7.09 (s, 1H), 7.11 (s, 1H), 7.12 (d, J = 2.0 Hz,1H), 7.22-7.26 (m, 1H), 7.41 (t, J = 8.1 Hz, 2H), 7.46 (s, 1H), 7.48 (s,1H), 8.24 (d, J = 2.0 Hz, 1H), 8.83 (br s, 1H). 417

4-(6-(4-(1- Acetylpiperidin- 4-yl)thiazol-2- ylamino)-5- phenoxypyridin-3-ylthio)-3- (trifluoromethyl) benzonitrile H¹ NMR (CDCl₃) δ 1.64-1.70(m, 2H), 2.04-2.12 (m, 5H), 2.70 (t, J = 12.8 Hz, 1H), 2.88 (t, J = 11.5Hz, 1H), 3.19 (t, J = 12.9 Hz, 1H), 3.91 (d, J = 13.7 Hz, 1H), 4.72 (d,J = 13.3 Hz, 1H), 6.53 (s, 1H), 6.97 (d, J = 8.4 Hz, 1H), 7.07 (d, J =8.0 Hz, 2H), 7.10 (s, 1H), 7.11-7.26 (m, 1H), 7.42 (t, J = 7.9 Hz, 2H),7.54 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 8.25 (d, J = 1.8 Hz, 1H), 8.88(br s, 1H). 418

4-(6-(4-(1- Acetylpiperidin- 4-yl)thiazol-2- ylamino)-5- phenoxypyridin-3-ylthio)-2- (trifluoromethyl) benzonitrile H¹ NMR (CDCl₃) δ 1.59-1.71(m, 2H), 2.04-2.12 (m, 5H), 2.70 (t, J = 11.5 Hz, 1H), 2.85-2.90 (m,1H), 3.15-3.22 (m, 1H), 3.91 (d, J = 13.7 Hz, 1H), 4.72 (d, J = 13.3 Hz,1H), 6.53 (s, 1H), 7.06 (s, 1H), 7.07 (s, 1H), 7.10 (d, J = 1.8 Hz, 1H),7.22- 7.25 (m, 2H), 7.39 (s, 1H), 7.42 (t, J = 8.1 Hz, 2H), 7.63 (d, J =8.4 Hz, 1H), 8.25 (d, J = 1.94 Hz, 1H), 8.87 (br s, 1H). 419

6-(6-(4-(1- Acetylpiperidin- 4-yl)thiazol-2- ylamino)-5- phenoxypyridin-3-ylthio)nicotino- nitrile H¹ NMR (CDCl₃) δ 1.62-1.71 (m, 2H), 2.04-2.12(m, 5H), 2.70 (t, J = 11.5 Hz, 1H), 2.84-2.90 (m, 1H), 3.15-3.22 (m,1H), 3.91 (d, J = 13.9 Hz, 1H), 4.72 (d, J = 13.5 Hz, 1H), 6.51 (s, 1H),7.03 (d, J = 8.4 Hz, 1H), 7.09 (s, 1H), 7.11 (s, 1H), 7.18 (d, J = 2.0Hz, 1H), 7.22-7.26 (m, 1H), 7.42 (t, J = 8.0 Hz, 2H), 7.66- 7.69 (m,1H), 8.25 (d, J = 1.8 Hz, 1H), 8.58 (d, J = 1.6 Hz, 1H), 8.84 (br s,1H). 420

5-(6-(4-(1- Acetylpiperidin- 4-yl)thiazol-2- ylamino)-5- phenoxypyridin-3-ylthio)-3- methoxypicolino- nitrile H¹ NMR (CDCl₃) δ 1.59-1.71 (m,2H), 2.03-2.12 (m, 5H), 2.70 (t, J = 11.5 Hz, 1H), 2.84-2.90 (m, 1H),3.18 (t, J = 11.7 Hz, 1H), 3.86 (s, 3H), 3.91 (d, J = 13.7 Hz, 1H), 4.72(d, J = 13.1 Hz, 1H), 6.52 (s, 1H), 6.96 (d, J = 1.8 Hz, 1H), 7.06 (s,1H), 7.07 (s, 1H), 7.09 (d, J = 13.3 Hz, 1H), 7.11-7.26 (m, 1H), 7.43(t, J = 8.0 Hz, 2H), 7.87 (d, J = 1.8 Hz, 1H), 8.26 (d, J = 1.8 Hz, 1H),8.85 (br s, 1H). 421

Ethyl 6-(6-(4-(1- acetylpiperidin-4- yl)thiazol-2- ylamino)-5-phenoxypyridin- 3-ylthio) picolinate dihydrochloride H¹ NMR (d₆ DMSO) δ1.28 (t, J = 7.0 Hz, 3H), 1.39-1.48 (m, 1H), 1.53-1.62 (m, 1H),1.91-2.00 (m, 5H), 2.63 (t, J = 12.6 Hz, 1H), 2.84 (t, J = 11.4 Hz, 1H),3.13 (t, J = 11.9 Hz, 1H), 3.87 (d, J = 13.7 Hz, 1H), 4.28-4.33 (m, 2H),4.42 (d, J = 13.1 Hz, 1H), 6.73 (s, 1H), 7.10-7.21 (m, 3H), 7.29 (d, J =7.8 Hz, 1H), 7.38 (t, J = 7.9 Hz, 2H), 7.42 (d, J = 1.8 Hz, 1H), 7.77(d, J = 7.6 Hz, 1H), 7.83 (t, J = 7.7 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H),11.13 (br s, 1H). 422

1-(4-(2-(3- Phenoxy-5-(6- (trifluoromethyl) pyridin-3-ylthio) pyridin-2-ylamino) thiazol-4- yl)piperidin-1- yl)ethanone H¹ NMR (d₆ DMSO) δ1.43-1.58 (m, 2H), 1.91-2.00 (m, 5H), 2.63 (t, J = 13.2 Hz, 1H), 2.83(br s, 1H), 3.13 (t, J = 11.9 Hz, 1H), 3.86 (d, J = 13.5 Hz, 1H), 4.42(d, J = 13.7 Hz, 1H), 6.74 (s, 1H), 7.12-7.16 (m, 3H), 7.38-7.41 (m,3H), 7.75-7.79 (m, 2H), 8.33 (s, 1H), 8.57 (s, 1H), 11.14 (s, 1H). 423

1-(4-(2-(5-(6- Bromothieno[3,2- b]pyridin-7- ylthio)-3- phenoxypyridin-2-ylamino) thiazol-4- yl)piperidin-1- yl)ethanone H¹ NMR (d₆ DMSO) δ1.42-1.46 (m, 1H), 1.55-1.58 (m, 1H), 1.93 (t, J = 16.7 Hz, 2H), 2.00(s, 3H), 2.63 (t, J = 12.4 Hz, 1H), 2.83 (br s, 1H), 3.12 (t, J = 12.8Hz, 1H), 3.86 (d, J = 13.1 Hz, 1H), 4.42 (d, J = 12.3 Hz, 1H), 6.74 (s,1H), 7.01 (d, J = 7.2 Hz, 2H), 7.12-7.14 (m, 1H), 7.34 (t, J = 7.3 Hz,2H), 7.41 (s, 1H), 7.50 (d, J = 5.5 Hz, 1H), 8.07 (d, J = 5.5 Hz, 1H),8.39 (s, 1H), 8.73 (s, 1H), 11.23 (s, 1H).

Example 4241-(4-(5-(5-(Thieno[3,2-b]pyridin-7-ylthio)-3-(2-(trifluoromethyl)phenoxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone

Prepared according to the method of Example 355, Example 13 and Example127. H¹ NMR (d₆ DMSO) δ 1.55-1.65 (m, 1H), 1.69-1.79 (m, 1H), 1.97-2.05(m, 5H), 2.77 (t, J=11.3 Hz, 1H), 3.05-3.10 (m, 1H), 3.20 (t, J=11.5 Hz,1H), 3.85 (d, J=13.5 Hz, 1H), 4.33 (d, J=13.1 Hz, 1H), 6.91 (d, J=5.1Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.36 (t, J=7.7 Hz, 1H), 7.48 (d, J=1.8Hz, 1H), 7.58 (d, J=5.5 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.78 (d, J=7.8Hz, 1H), 8.15 (d, J=5.5 Hz, 1H), 8.48 (d, J=5.1 Hz, 1H), 8.54 (d, J=1.8Hz, 1H), 12.62 (s, 1H).

Example 425 tert-butyl4-(2-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-thio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate

Step A: Preparation of tert-butyl4-(2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate:1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (3.00 g, 8.77 mmol;prepared according to Example 179, Step D), TEA (2.08 mL, 14.9 mmol) andtert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (3.49 g, 11.4 mmol)were refluxed in ethanol (75 mL) for 2 hours. The reaction was cooled toroom temperature and filtered to afford the title compound (3.6 g, 74.7%yield).

Step B: tert-butyl4-(2-(3-(4-fluorophenoxy)-5-(3-methoxy-3-oxopropylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate: Preparedaccording to the method of Example 13.

Step C: tert-butyl4-(2-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate: Preparedaccording to the method of Example 127. ¹H NMR (d₆-DMSO) δ 11.21 (bs,1H), 8.49 (d, 1H), 8.36 (d, 1H), 8.16 (d, 1H), 7.59 (d, 1H), 7.39 (d,1H), 7.25-7.15 (m, 4H), 6.90 (d, 1H), 6.74 (s, 1H), 4.03 (m, 2H), 2.81(m, 3H), 1.93 (m, 2H), 1.50 (m, 2H), 1.41 (s, 9H).

Example 426N-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-yl)-4-(piperidin-4-yl)thiazol-2-aminedihydrochloride

Prepared according to the method of Example 271. ¹H NMR (d₆-DMSO) δ11.26 (bs, 1H), 8.79 (m, 1H), 8.59 (m, 1H), 8.53 (d, 1H), 8.38 (d, 1H),8.23 (d, 1H), 7.62 (d, 1H), 7.43 (d, 1H), 7.26-7.16 (m, 4H), 6.97 (d,1H), 6.82 (s, 1H), 3.33 (d, 2H), 3.06-2.86 (m, 3H), 2.13 (d, 2H), 1.80(m, 2H).

The following compounds also were made according to the method ofExample 272.

Example R Name NMR data 427

1-(4-(2-(3-(4- fluorophenoxy)-5- (thieno[3,2-b]pyridin-7-ylthio)pyridin-2- ylamino)thiazol-4- yl)piperidin-1-yl)ethanonehydrochloride ¹H NMR (d₆-DMSO) δ 11.21 (bs, 1H), 8.50 (d, 1H), 8.37 (d,1H), 8.18 (d, 1H), 7.60 (d, 1H), 7.41 (d, 1H), 7.25-7.14 (m, 4H), 6.92(d, 1H), 6.74 (s, 1H), 4.33 (d, 1H), 3.87 (d, 1H), 3.13 (t, 1H), 2.85(m, 1H), 2.64 (t, 1H), 2.01 (s, 3H), 1.95 (m, 2H), 1.59 (m, 1H), 1.45(m, 1H). 428

2-(4-(2-(3-(4- fluorophenoxy)-5- (thieno[3,2-b]pyridin-7-ylthio)pyridin-2- ylamino)thiazol-4- yl)piperidin-1-yl)-2- oxoethylacetate ¹H NMR (d₆-DMSO) δ 11.24 (s, 1H), 8.49 (d, 1H), 8.36 (d, 1H),8.16 (d, 1H), 7.59 (d, 1H), 7.40 (d, 1H), 7.26-7.14 (m, 4H), 6.90 (d,1H), 6.76 (s, 1H), 4.79 (m, 2H), 4.36 (d, 1H), 3.77 (d, 1H), 3.12 (t,1H), 2.87 (m, 1H), 2.72 (t, 1H), 2.08 (s, 3H), 1.96 (m, 2H), 1.62 (m,1H), 1.49 (m, 1H). 429

isopropyl 4-(2-(3-(4- fluorophenoxy)-5- (thieno[3,2-b]pyridin-7-ylthio)pyridin-2- ylamino)thiazol-4- yl)piperidin-1- carboxylatehydrochloride ¹H NMR (d₆-DMSO) δ 8.61 (d, 1H), 8.41 (d, 1H), 8.39 (d,1H), 7.71 (d, 1H), 7.48 (d, 1H), 7.26-7.17 (m, 4H), 7.11 (d, 1H), 6.79(s, 1H), 4.77 (m, 1H), 4.04 (d, 2H), 2.85 (m, 3H), 1.94 (d, 2H), 1.51(m, 2H), 1.19 (d, 6H). 430

2-(dimethylamino)-1-(4- (2-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7- ylthio)pyridin-2- ylamino)thiazol-4-yl)piperidin-1-yl)ethanone dihydrochloride ¹H NMR (d₆-DMSO) δ 9.60 (bs,1H), 8.58 (d, 1H), 8.40 (d, 1H), 8.33 (d, 1H), 7.68 (d, 1H), 7.47 (d,1H), 7.27-7.17 (m, 4H), 7.05 (d, 1H), 6.78 (s, 1H), 4.45- 4.28 (m, 3H),3.67 (d, 2H), 3.18 (t, 1H), 2.93 (m, 1H), 2.82 (d, 6H), 2.04 (d, 2H),1.65 (m, 1H), 1.50 (m, 1H) 431

N-(3-(4-fluorophenoxy)-5- (thieno[3,2-b]pyridin-7-ylthio)pyridin-2-yl)-4-(1- (methylsulfonyl)piperidin-4-yl)thiazol-2-amine hydrochloride ¹H NMR (d₆-DMSO) δ 8.57 (d, 1H), 8.40(d, 1H), 8.32 (d, 1H), 7.67 (d, 1H), 7.46 (d, 1H), 7.26-7.16 (m, 4H),7.05 (d, 1H), 6.80 (s, 1H), 3.64 (d, 2H), 2.88 (s, 3H), 2.84 (t, 2H),2.73 (m, 1H), 2.08 (d, 2H), 1.66 (m, 2H)

The following compounds were also made according to the method ofExample 282.

Example R Name NMR Data 432

N-(1-(4-(2-(3-(4- fluorophenoxy)-5- (thieno[3,2-b]pyridin-7-ylthio)pyridin-2- ylamino)thiazol-4- yl)piperidin-1-yl)-1-oxopropan-2-yl)acetamide ¹H NMR (d₆-DMSO) δ 8.60 (d, 1H), 8.41 (d, 1H),8.37 (d, 1H), 8.13 (t, 1H), 7.70 (d, 1H), 7.42 (s, 1H), 7.27-7.17 (m,4H), 7.10 (d, 1H), 6.73 (d, 1H), 4.77 (m, 1H), 4.44 (m, 1H), 3.98 (m,1H), 3.15 (t, 1H), 2.89 (m, 1H), 2.70 (m, 1H), 1.98 (m, 2H), 1.82 (s,3H), 1.63-1.40 (m, 2H), 1.15 (t, 3H). 433

N-(2-(4-(2-(3-(4- fluorophenoxy)-5- (thieno[3,2-b]pyridin-7-ylthio)pyridin-2- ylamino)thiazol-4- yl)piperidin-1-yl)-2-oxoethyl)acetamide hydrochloride ¹H NMR (d₆-DMSO) δ 8.58 (d, 1H), 8.40(d, 1H), 8.33 (d, 1H), 7.96 (m, 1H), 7.68 (d, 1H), 7.46 (d, 1H),7.26-7.16 (m, 4H), 7.06 (d, 1H), 6.77 (s, 1H), 4.41 (d, 1H), 4.01-3.84(m, 3H), 3.12 (t, 1H), 2.88 (t, 1H), 2.71 (t, 1H), 1.97 (m, 2H), 1.87(s, 3H), 1.60 (m, 1H), 1.47 (m, 1H).

Example 4344-(1-(2-aminoethylsulfonyl)piperidin-4-yl)-N-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-yl)thiazol-2-aminedihydrochloride

Step A: Preparation of2-(2-(4-(2-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-ylsulfonyl)ethyl)isoindoline-1,3-dione:Prepared according to the method of Example 288, Step A.

Step B: Preparation of4-(1-(2-aminoethylsulfonyl)piperidin-4-yl)-N-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-yl)thiazol-2-aminedihydrochloride: Prepared according to the method of Example 288, Step Busing hydrazine monohydrate. ¹H NMR (d₆-DMSO)S 8.58 (d, 1H), 8.41 (d,1H), 8.34 (d, 1H), 8.15 (bs, 2H), 8.07 (bs, 1H), 7.89 (m, 1H), 7.69 (d,1H), 7.47 (d, 1H), 7.27-7.17 (m, 4H), 7.07 (d, 1H), 6.81 (s, 1H), 3.70(d, 1H), 3.43 (t, 2H), 3.17 (m, 2H), 3.00 (t, 2H), 2.80 (m, 1H), 2.08(d, 2H), 1.65 (m, 2H).

Example 4354-(2-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-sulfonamide2,2,2-trifluoroacetate

Prepared according to the method of Example 287 from3-(4-fluorophenoxy)-N-(4-(piperidin-4-yl)thiazol-2-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine.¹H NMR (d₆-DMSO) δ 11.22 (s, 1H), 8.49 (d, 1H), 8.37 (d, 1H), 8.16 (d,1H), 7.59 (d, 1H), 7.41 (d, 1H), 7.26-7.14 (m, 4H), 6.90 (d, 1H), 6.78(s, 1H), 6.73 (s, 2H), 3.53 (d, 2H), 2.65 (m, 3H), 2.05 (m, 2H), 1.69(m, 2H).

Example 4364-(2-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxamidehydrochloride

Prepared according to the method of Example 280 from3-(4-fluorophenoxy)-N-(4-(piperidin-4-yl)thiazol-2-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine.¹H NMR (d₆-DMSO) δ 8.62 (d, 1H), 8.43 (m, 2H), 7.73 (d, 1H), 7.50 (d,1H), 7.27-7.18 (m, 4H), 7.14 (d, 1H), 6.79 (s, 1H), 4.01 (d, 2H), 2.78(m, 3H), 1.88 (d, 2H), 1.50 (m, 2H).

Example 437 tert-butyl4-(2-(3-(4-fluorophenoxy)-5-(3-methylisoxazolo[5,4-b]pyridin-4-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate

Prepared according to the method of Example 127 from tert-butyl4-(2-(3-(4-fluorophenoxy)-5-(3-methoxy-3-oxopropylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate.¹H NMR (d₆-DMSO) δ 11.25 (bs, 1H), 8.35 (d, 1H), 8.32 (d, 1H), 7.40 (d,1H), 7.27-7.21 (m, 4H), 6.76 (s, 1H), 6.71 (d, 1H), 4.02 (m, 2H), 2.83(m, 3H), 2.69 (s, 3H), 1.94 (d, 2H), 1.50 (m, 2H), 1.41 (s, 9H).

Example 438N-(3-(4-fluorophenoxy)-5-(3-methylisoxazolo[5,4-b]pyridin-4-ylthio)pyridin-2-yl)-4-(piperidin-4-yl)thiazol-2-aminedihydrochloride

Prepared according to the method of Example 271 from tert-butyl4-(2-(3-(4-fluorophenoxy)-5-(3-methylisoxazolo[5,4-b]pyridin-4-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate.¹H NMR (d₆-DMSO) δ 8.88 (m, 1H), 8.70 (m, 1H), 8.36 (d, 1H), 8.32 (d,1H), 7.42 (d, 1H), 7.29-7.10 (m, 4H), 6.83 (s, 1H), 6.72 (d, 1H), 3.33(d, 2H), 3.06-2.85 (m, 3H), 2.69 (s, 3H), 2.14 (d, 2H), 1.81 (m, 2H).

The following compounds were also made according to the procedure ofExample 272.

Example R Name NMR Data 439

1-(4-(2-(3-(4- fluorophenoxy)-5-(3- methylisoxazolo[5,4-b]pyridin-4-ylthio)pyridin- 2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone hydrochloride, ¹H NMR (d₆-DMSO) δ 11.28 (bs,1H), 8.35 (d, 1H), 8.32 (d, 1H), 7.41 (d, 1H), 7.27-7.19 (m, 4H), 6.76(s, 1H), 6.72 (d, 1H), 4.43 (d, 1H), 3.87 (d, 1H), 3.14 (t, 1H), 2.86(m, 1H), 2.69 (s, 3H), 2.65 (m, 1H), 2.01 (s, 3H), 1.95 (m, 2H), 1.60(m, 1H), 1.45 (m, 1H). 440

2-(dimethylamino)-1-(4-(2- (3-(4-fluorophenoxy)-5-(3-methylisoxazolo[5,4- b]pyridin-4-ylthio)pyridin- 2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone dihydrochloride, ¹H NMR (d₆-DMSO) δ 11.23(bs, 1H), 9.54 (bs, 1H), 8.36 (d, 1H), 8.32 (d, 1H), 7.42 (d, 1H),7.28-7.19 (m, 4H), 6.78 (s, 1H), 6.71 (d, 1H), 4.42 (d, 1H), 4.30 (m,2H), 3.66 (d, 1H), 3.19 (t, 1H), 2.91 (m, 2H), 2.81 (d, 6H), 2.69 (s,3H), 2.04 (d, 2H), 1.65 (m, 1H), 1.51 (m, 1H)

Example 441 methyl4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylatehydrochloride

Prepared according to the method of Example 272 from3-phenoxy-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(pyridin-2-ylthio)pyridin-2-amine.¹H NMR (d₆-DMSO) δ 12.33 (s, 1H), 8.39 (d, 1H), 8.37 (m, 1H), 7.66 (dt,1H), 7.47 (d, 1H), 7.42 (d, 2H), 7.21-7.11 (m, 5H), 3.98 (m, 2H), 3.60(s, 3H), 3.01 (m, 3H), 1.99 (d, 2H), 1.65 (m, 2H).

Example 4421-(4-(2-(5-(3-methylthieno[3,2-b]pyridin-7-ylthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone

Step A: 3-amino-4-methylthiophene-2-carboxylic acid: Methyl3-amino-4-methylthiophene-2-carboxylate (4.67 g, 27.3 mmol) and NaOH (2Nin H₂O, 68 mL, 136 mmol) were stirred at 100° C. for 1 hour. Thesolution was cooled to 0° C. and acidified to pH=5 with addition ofconcentrated HCl solution to form a precipitant. The solution wasfiltered and the solid was dried under vacuum to give the title compound(2.8 g, 65%).

Step B: 4-methylthiophen-3-amine: 3-amino-4-methylthiophene-2-carboxylicacid (5.64 g, 36 mmol) in HCl (6N in H₂O, 30 mL, 179 mmol) was stirredat 50° C. overnight. It was cooled to room temperature and neutralizedby the addition of solid NaHCO₃. The solution was extracted withdichloromethane (2 times), dried over Na₂SO₄, filtered and concentratedto yield the title compound (3.8 g, 94% yield).

Step C:2,2-dimethyl-5-((4-methylthiophen-3-ylamino)methylene)-1,3-dioxane-4,6-dione:A stirred solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (4.85 g, 34mmol) in trimethoxymethane (37 mL, 337 mmol) was heated to 90° C. undernitrogen. After 2 hours, a solution was 4-methylthiophen-3-amine (3.81g, 34 mmol) was added (as a solution in trimethoxymethane (37 mL, 337mmol). The reaction stirred at 90° C. for 6 hours and then was allowedto cool to room temperature and concentrated. The material was placed inthe refrigerator where it solidified after two days to obtain the titlecompound (9 g, quantitative).

Step D: 3-methylthieno[3,2-b]pyridin-7-ol: A solution of Dowtherm A (7mL) was heated in oil bath at 235° C. under nitrogen.2,2-dimethyl-5-((4-methylthiophen-3-ylamino)methylene)-1,3-dioxane-4,6-dione(5.0 g, 19 mmol) was added in portions over a 20 minutes period. Afterthe last portion was added, the solution stirred at 235° C. for another5 minutes. The solution was removed from the oil bath and allowed tocool to room temperature. Upon cooling, the product precipitated out ofsolution. Diethyl ether was added and the solid was filtered and driedto give the title compound (3.2 g) with residual amounts of Dowtherm Aremaining.

Step E: 7-chloro-3-methylthieno[3,2-b]pyridine: Phosphorous oxychloride(2.2 mL, 24 mmol) in 1,2-dichloroethane (12 mL) was charged with3-methylthieno[3,2-b]pyridin-7-ol (2.0 g, 12 mmol). The reaction stirredovernight at reflux under nitrogen. The mixture was the cooled andconcentrated. Saturated NaHCO₃ solution was carefully added toneutralize the residue. The biphasic mixture was extracted withdichloromethane, dried, and concentrated. Flash chromatography (15%EtOAc/hexanes) gave the title compound (1.23 g, 55%).

Step F:1-(4-(2-(5-(3-methylthieno[3,2-b]pyridin-7-ylthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone:7-chloro-3-methylthieno[3,2-b]pyridine (0.072 g, 0.39 mmol) and methyl3-(6-(4-(1-acetylpiperidin-4-yl)thiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate(0.20 g, 0.39 mmol) were dissolved in DMSO (3 mL). The solution wasdegassed for 15 minutes under nitrogen. KOtBu (0.13 g, 1.2 mmol) wasadded and the reaction stirred at room temperature for two hours. Thesolution was quenched with water, extracted with dichloromethane, dried,and concentrated. Flash chromatography gave the title compound (0:100 g,44% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.60-1.72 (m, 2H), 2.03-2.09 (m,2H), 2.11 (s, 31H), 2.51 (s, 3H), 2.66-2.73 (m, 1H), 2.83-2.90 (m, 1H),3.15-3.22 (m, 1H), 3.88-3.94 (m, 1H), 4.70-4.73 (m, 1H), 6.51 (s, 1H),6.75 (d, 1H), 7.05 (d, 2H), 7.17-7.25 (m, 2H), 7.36-7.40 (m, 3H), 8.30(d, 1H), 8.48 (d, 1H), 8.84 (bs, 1H).

Example 4431-(4-(2-(5-(5-chlorothieno[3,2-b]pyridin-7-ylthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone

Steps A and B: Thiophen-3-amine: Prepared according to the method ofExample 442, Steps A and B, using methyl 3-aminothiophene-2-carboxylateas the starting material.

Step C and D:1-(4-(2-(5-(5-chlorothieno[3,2-b]pyridin-7-ylthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone:Prepared according to the method of Example 442, Steps E and F. ¹H NMR(400 MHz, CDCl₃) δ 1.60-1.73 (m, 2H), 2.05-2.10 (m, 2H), 2.12 (s, 3H),2.66 (t, 1H), 2.85-2.91 (m, 1H), 3.17 (t, 1H), 3.91 (d, 1H), 4.71 (d,1H), 6.53 (s, 1H), 6.67 (s, 1H), 7.08 (d, 2H), 7.17 (s, 1H), 7.22-7.26(m, 1H), 7.41 (t, 2H), 7.47 (d, 1H), 7.76 (d, 1H), 8.32 (s, 1H), 8.96(s, 1H).

Example 444 Preparation of tert-butyl4-((2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)methyl)-3-oxopiperazine-1-carboxylate

Step A: Preparation of tert-Butyl4-(3-chloro-2-hydroxypropyl)-3-oxopiperazine-1-carboxylate. In a 50 0 mlround bottom flask with magnetic stirrer 4-Boc-piperazinone (5.08 g,25.4 mmol) was dissolved in THF (100 mL) and cooled to −78° C.Butyllithium (1.6M in hexanes) (15.9 mL, 25.4 mmol) was added then andthe mixture agitated for 30 minutes at −78° C. Boron trifluorideethereate (3.19 mL, 25.4 mmol) was added slowly and then epichlorohydrin(1.99 mL, 25.4 mmol). The mixture was agitated for 1 hour at −78° C. andthen allowed to warm up and agitated overnight. Reaction was quenchedwith saturated ammonium chloride, extracted three times with ethylacetate, extracts washed with brine and evaporated. Purified by columnchromatography on silica gel, eluting with 3% MeOH/CH₂Cl₂ to give thetitle compound (3.34 g, 45% yield).

Step B: Preparation of tert-Butyl4-(3-chloro-2-oxopropyl)-3-oxopiperazine-1-carboxylate. In a 125 mlround-bottom flask equipped with a magnetic stirrer tert-butyl4-(3-chloro-2-hydroxypropyl)-3-oxopiperazine-1-carboxylate (3.30 g, 11.3mmol) was dissolved in acetonitrile (10 ml) and Dess-Martin periodinane(5.26 g, 12.4 mmol) was added. After agitating for 3 hours the mixturewas diluted with ethyl acetate (100 ml) and washed with sodiumbicarbonate and brine, dried and evaporated. Purified by columnchromatography and eluting with 3% MeOH/CH₂Cl₂ to give the titlecompound (0.600 g, 18.31% yield).

Step C: Preparation of tert-Butyl4-((2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)methyl)-3-oxopiperazine-1-carboxylate.In a 20 mL scintillation vial equipped with magnetic stirrer1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (0.25 g, 0.73 mmol)was suspended in ethanol (5 ml) and tert-butyl4-(3-chloro-2-oxopropyl)-3-oxopiperazine-1-carboxylate (0.32 g, 1.10mmol) was added followed by DIEA (0.22 mL, 1.28 mmol). Resulting mixturewas heated to 60° C. and agitated for 3 hours. Mixture was then dilutedwith ethyl acetate and washed with sodium bicarbonate solution, brine,dried and evaporated. Purified by column chromatography on silica gel,eluting with 50-100% ethyl acetate/hexane to give the title compound(0.106 g, 25.1% yield). ¹H NMR (CDCl₃) δ 1.41 (s, 9H), 2.79-3.42 (m,6H), 6.55 (s, 2H), 7.03-7.12 (m, 4H), 8.12 (s, 1H), 8.95 (bs, 1H).

Example 445 Preparation of1-((2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)methyl)piperazin-2-one

In a 20 mL scintillation vial equipped with magnetic stirrer tert-butyl4-((2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)methyl)-3-oxopiperazine-1-carboxylate(0.020 g, 0.035 mmol) was dissolved in 1 ml of CH₂Cl₂ and 4M HCl indioxane (0.50 mL, 2.0 mmol) was added. The resulting mixture wasagitated for 2 hours, diluted with 5 mL of ether and the solvent wasdecanted off. The residue was dried to provide the title compound (0.012g, 73% yield). ¹H NMR (d₆-DMSO)S 3.25-3.78 (m, 6H), 6.99 (s, 1H),7.28-7.36 (m, 4H), 8.23 (s, 1H), 8.34 (s, 1H), 10.24 (s, 2H).

Example 4461-(4-(2-(3-phenoxy-5-(thieno[2,3-d]pyrimidin-4-ylthiopyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone

Step A: Thieno[2,3-d]pyrimidin-4(3H)-one: Methyl2-aminothiophene-3-carboxylate (10 g, 64 mmol) was charged withformamide (50 mL). The reaction was heated at 190° C. under nitrogen for3 hours. The solution was cooled to room temperature. The slurry waspoured into 125 mL of water and extracted with chloroform:isopropylalcohol mixture (2 times). The solution was concentrated and trituratedto afford the title compound (2.25 g, 23%).

Step B: 4-Chlorothieno[2,3-d]pyrimidine:Thieno[2,3-d]pyrimidin-4(3H)-one (1.2 g, 7.9 mmol) was diluted in1,2-dichloroethane (10 mL). Phosphorous oxychloride (1.4 mL, 15.7 mmol)was added. The reaction was stirred at 90° C. for 16 hours. Anadditional equivalent of phosphorous oxychloride (0.7 mL, 7.9 mmol) wasadded and the solution continued stirring for 4 hours. The solution wascooled, concentrated, and neutralized with saturated NaHCO₃ solution.The material was extracted with a chloroform:isopropyl alcohol mixtureand the organic layer was separated and concentrated. Flashchromatography gave the title compound (0.39 g, 29%).

Step C:1-(4-(2-(3-phenoxy-5-(thieno[2,3-d]pyrimidin-4-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-yl)ethanone:4-chlorothieno[2,3-d]pyrimidine (0.050 g, 0.29 mmol) and methyl3-(6-(4-(1-acetylpiperidin-4-yl)thiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate(0.15 g, 0.29 mmol) were dissolved in DMSO (3 mL). The solution wasdegassed for 15 minutes. KOtBu (0.098 g, 0.88 mmol) was added and thereaction stirred at room temperature for two hours. The solution wasquenched with water, extracted with dichloromethane, dried, andconcentrated. Flash chromatography gave the title compound (0.075, 46%).¹H NMR (400 MHz, CDCl₃) δ 1.60-1.72 (m, 2H), 2.08-2.15 (m, 2H), 2.11 (m,3H), 2.65-2.75 (m, 1H), 2.82-2.93 (m, 1H), 3.15-3.24 (m, 1H), 3.91 (d,1H), 4.72 (d, 1H), 6.49 (s, 1H), 7.15 (d, 2H), 7.19 (t, 1H), 7.27-7.29(m, 1H), 7.36-7.42 (m, 3H), 7.53 (d, 1H), 8.27 (d, 1H), 8.68 (s, 1H),8.81 (s, 1H).

Example 447 tert-butyl4-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)piperidine-1-carboxylate

Step A: Preparation of tert-butyl4-(2-(methoxy(methyl)amino)-2-oxoethyl)piperidine-1-carboxylate:N-methoxymethanamine hydrochloride (2.61 g, 26.7 mmol),N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (5.91 g, 30.8 mmol), 1H-benzo[d][1,2,3]triazol-1-olhydrate (4.72 g, 30.8 mmol), and triethylamine (11.5 mL, 82.2 mmol) wereadded sequentially to a solution of2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (5.00 g, 20.6 mmol)in methylene chloride (150 mL) at 0° C. Stirred at ambient temperaturefor 4 hours, and partitioned between ethyl acetate and 2N HCl. Washedthe organic layer again with 2N HCl, twice with 2N NaOH, brine, dried,and concentrated to afford the title compound (5.93 g, 101% yield) as aclear colorless viscous oil.

Step B: Preparation of tert-butyl4-(2-oxopropyl)piperidine-1-carboxylate: Added dropwise 3.0 Mmethylmagnesium chloride in THF (8.63 mL, 25.9 mmol) to a solution oftert-butyl4-(2-(methoxy(methyl)amino)-2-oxoethyl)piperidine-1-carboxylate (5.93 g,20.7 mmol) in THF (100 mL) at 0° C. Warmed to ambient temperature andstirred for 90 minutes. Partitioned between ether and 2N HCl, washed theorganic layer twice with water, brine, dried, and concentrated to affordthe title compound (4.95 g, 99.1% yield) as a clear oil.

Step C: Preparation of tert-butyl4-(2-(trimethylsilyloxy)allyl)piperidine-1-carboxylate: To a cooled(−78° C.) solution of LDA (12.3 mL, 24.6 mmol) in THF (50 mL) was addeddropwise over 40 minutes a solution of tert-butyl4-(2-oxopropyl)piperidine-1-carboxylate (4.95 g, 20.5 mmol) in THF (20mL). After an additional 25 minutes, chlorotrimethylsilane (5.21 mL,41.0 mmol) was added dropwise over 20 minutes. After stirring for anhour, the reaction was poured into saturated NaHCO₃ and extracted withether (2×400 mL). The combined ether layers were washed with brine,dried, filtered and concentrated to afford the title compound (6.95 g,108% yield) which was used as is in the next step.

Step D: Preparation of tert-butyl4-(3-bromo-2-oxopropyl)piperidine-1-carboxylate: To a solution oftert-butyl 4-(2-(trimethylsilyloxy)allyl)piperidine-1-carboxylate (6.43g, 20.5 mmol) in THF (100 mL) at 0° C. was added sodium bicarbonate(2.58 g, 30.7 mmol) followed by 1-bromopyrrolidine-2,5-dione (3.65 g,20.5 mmol). Warmed to ambient temperature and stirred 90 minutes.Partitioned between ether (150 mL) and saturated sodium bicarbonate. Theaqueous layer was reextracted with ether (100 mL). The combined organiclayers were washed with saturated bicarbonate, brine, dried, andconcentrated to afford the title compound (7.2 g, 110% yield) as ayellow oil. Purity was 85% with the major impurity being succinimide.The crude material was used in the next step.

Step E: Preparation of tert-butyl4-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)piperidine-1-carboxylate:Heated a mixture tert-butyl4-(3-bromo-2-oxopropyl)piperidine-1-carboxylate (1.38 g, 4.32 mmol),1-(5-bromo-3-phenoxypyridin-2-yl)thiourea (1.0 g, 3.08 mmol),triethylamine (0.731 mL, 5.24 mmol), and ethanol (50 mL) at refluxovernight. Cooled to ambient temperature and partitioned between intowater and ethyl acetate. Washed the organic layer with water, brine,dried and concentrated. Purified by MPLC (Biotage) eluting with 3:1hexane:ethyl acetate to afford the title compound (1.54 g, 92%) as awhite powder: ¹H NMR (CDCl₃) δ 8.66 (s, 1H), 8.13 (s, 1H), 7.43 (t, 2H),7.25 (t, 1H), 7.12 (s, 1H), 7.06 (d, 2H), 6.45 (s, 1H), 4.08 (m, 2H),2.67 (m, 2H), 2.56 (d, 2H), 1.85 (m, 1H), 1.66 (m, 2H), 1.44 (s, 9H),1.15 (m, 2H).

The following compounds were prepared from the appropriate carboxylicacid according to the procedure of Example 447.

Example Structure Name ¹H NMR 448

tert-butyl 3-(2-(5- bromo-3- phenoxypyridin-2- ylamino)thiazol-4-yl)piperidine-1- carboxylate ¹H NMR (CDCl₃) δ 8.64 (s, 1H), 8.12 (s,1H), 7.44 (t, 2H), 7.25 (t, 1H), 7.06-7.11 (m, 3H), 6.53 (s, 1H), 4.22(m, 1H), 4.02 (m, 1H), 2.99 (m, 1H), 2.84-2.90 (m, 2H), 2.10 (m, 1H),1.72 (m, 3H), 1.45 (s, 9H). 449

tert-butyl 3-(2-(5- bromo-3- phenoxypyridin-2- ylamino)thiazol-4-yl)pyrrolidine-1- carboxylate ¹H NMR (d₆-DMSO) δ 10.93 (s, 1H), 8.17 (s,1H), 7.36-7.41 (m, 3H), 7.17 (t, 1H), 7.04 (d, 2H), 6.75 (s, 1H), 3.58(m, 1H), 3.23-3.40 (m, 4H), 2.12 (m, 1H), 1.97 (m, 1H), 1.36 (s, 9H).450

tert-butyl 4-(2-(5- bromo-3-(4- cyanophenoxy) pyridin-2-ylamino)thiazol-4- yl)piperidine-1- carboxylate ¹H NMR (CDCl₃) δ 8.45(s, 1H), 8.26 (s, 1H), 7.71 (d, 2H), 7.31 (s, 1H), 7.14 (d, 2H), 6.47(s, 1H), 4.17 (m, 2H), 2.69-2.87 (m, 3H), 1.97 (m, 2H), 1.57 (m, 2H),1.46 (s, 9H).

Example 451 tert-butyl3-(5-(5-bromo-3-phenoxypyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)pyrrolidine-1-carboxylate

A 40 mL flask was charges with tert-butyl3-(chloro(methylsulfonyl-oxyimino)methyl)pyrrolidine-1-carboxylate (1.60g, 4.90 mmol) and acetonitrile (25 mL). Added pyridine (1.22 mL, 15.1mmol) and isothiocyanatosodium (0.398 g, 4.90 mmol) and heated to 40° C.for 45 minutes. Added 5-bromo-3-phenoxypyridin-2-amine (1.00 g, 3.77mmol) and heated at 60° C. overnight. The reaction was cooled to ambienttemperature, poured into water and extracted with EtOAc (100 mL). Theorganic layer were dried with sodium sulfate, filtered and concentrated.The residue was purified by MPLC (Biotage) eluting with 3:1 hexane:ethylacetate to afford tert-butyl3-(5-(5-bromo-3-phenoxypyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)pyrrolidine-1-carboxylateas a light yellow/off white solid: ¹H NMR (d₆-DMSO) δ 12.21 (s, 1H),8.34 (s, 1H), 7.48 (s, 1H), 7.39 (t, 2H), 7.18 (t, 1H), 7.07 (d, 2H),3.42-3.63 (m, 3H), 3.36 (m, 1H), 2.02-2.21 (m, 3H), 1.35 (s, 9H).

Example 452 tert-butyl4-((2-(5-(3-methoxy-3-oxopropylthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)piperidine-1-carboxylate

The atmosphere above a mixture of tert-butyl4-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)piperidine-1-carboxylate(1.52 g, 2.79 mmol), N-ethyl-N-isopropylpropan-2-amine (0.971 mL, 5.57mmol), 4,5-bis(diphenylphosphino)-9,9-diethyl-9H-xanthene (0.161 g,0.279 mmol), and dioxane (25 mL) was purged with nitrogen. Methyl3-mercaptopropanoate (0.332 mL, 3.07 mmol) and Pd₂dba₃ (0.128 g, 0.139mmol) were added, and the reaction was heated at 95° C. overnight. Thereaction was cooled to ambient temperature and filtered through celite.The filtrate was concentrated and purified by MPLC (Biotage) elutingwith 3:2 hexane:ethyl acetate to afford the title compound (1.54 g,94.5% yield) as a tacky white solid: ¹H NMR (CDCl₃) δ 8.70 (s, 1H), 8.16(s, 1H), 7.40 (t, 2H), 7.24 (t, 1H), 7.14 (s, 1H), 7.06 (d, 2H), 6.46(s, 1H), 4.08 (m, 2H), 3.65 (s, 3H), 2.99 (t, 2H), 2.67 (m, 2H), 2.56(d, 2H), 2.55 (t, 2H), 1.85 (m, 1H), 1.66 (m, 2H), 1.45 (s, 9H), 1.16(m, 2H).

The following compounds were prepared from the appropriate bromideaccording to the procedure of Example 452.

Ex- ample Structure Name ¹H NMR 453

tert-butyl 4-(2- (3-(4-cyano- phenoxy)- 5-(3-methoxy- 3-oxopropyl-thio)pyridin-2- ylamino)thiazol- 4-yl)piperidine- 1-carboxylate ¹H NMR(CDCl₃) δ 8.46 (s, 1H), 8.27 (s, 1H), 7.70 (d, 2H), 7.31 (s, 1H), 7.13(d, 2H), 6.47 (s, 1H), 4.19 (m, 2H), 3.66 (s, 3H), 3.04 (t, 2H),2.71-2.85 (m, 3H), 2.59 (t, 2H), 1.97 (m, 2H), 1.59 (m, 2H), 1.46 (s,9H). 454

tert-butyl 3-(5- (5-(3-methoxy- 3-oxopropyl- thio)-3-phen- oxypyridin-2-ylamino)-1,2,4- thiadiazol-3- yl)pyrrolidine- 1-carboxylate ¹H NMR(CDCl₃) δ 9.02 (s, 1H), 8.0 (s, 1H),3 7.44 (t, 2H), 7.28 (t, 1H), 7.18(s, 1H), 7.09 (d, 2H), 3.82 (m, 1H), 3.67 (s, 3H), 3.54-3.67 (m, 2H),3.43 (m, 1H), 3.04 (t, 2H), 2.57 (t, 2H), 2.22-2.35 (m, 3H), 1.46 (s,9H). 455

tert-butyl 3-(2- (5-(3-methoxy- 3-oxopropyl- thio)-3-phen- oxypyridin-2-ylamino)thiazol- 4-yl)piperidine- 1-carboxylate ¹H NMR (CDCl₃) δ 8.68(s, 1H), 8.15 (s, 1H), 7.42 (t, 2H), 7.23 (t, 1H), 7.13 (s, 1H), 7.07(d, 2H), 6.53 (s, 1H), 4.21 (m, 1H), 4.00 (m, 1H), 3.65 (s, 3H), 2.99(t, 2H), 2.76-2.90 (m, 4H), 2.55 (t, 2H), 2.09 (m, 1H), 1.71 (m, 2H),1.46 (s, 9H). 456

tert-butyl 3-(2- (5-(3-methoxy- 3-oxopropyl- thio)-3-phen- oxypyridin-2-ylamino)thiazol- 4-yl)pyrrolidine- 1-carboxylate ¹H NMR (CDCl₃) δ 8.69(s, 1H), 8.16 (s, 1H), 7.42 (t, 2H), 7.24 (t, 1H), 7.13 (s, 1H), 7.08(d, 2H), 6.54 (s, 1H), 3.76 (m, 1H), 3.65 (s, 3H), 3.64 (m, 1H), 3.50(m, 1H), 3.41 (m, 2H), 2.99 (t, 2H), 2.56 (t, 2H), 2.24 (m, 1H), 2.11(m, 1H), 1.46 (s, 9H).

Example 457 tert-butyl4-((2-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)methyl)piperidine-1-carboxylate

Added potassium 2-methylpropan-2-olate (0.443 g, 3.95 mmol) to asolution of 7-chlorothieno[3,2-b]pyridine (0.268 g, 1.58 mmol) andtert-butyl4-((2-(5-(3-methoxy-3-oxopropylthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)piperidine-1-carboxylate(0.77 g, 1.32 mmol) in DMSO (8 mL). The reaction was stirred for twohours, then set aside to react at ambient temperature for 60 hours. Thereaction was partitioned between ethyl acetate and saturated ammoniumchloride. Washed the organic layer twice with water and brine, dried,and concentrated. The residue was purified by MPLC (Biotage) elutingwith 1:1 hexane:ethyl acetate. The major UV active component with an Rfof 0.3 was collected and concentrated to afford the title compound(0.810 g, 97.4% yield) as a white powder: ¹H NMR (CDCl₃) δ 8.88 (s, 1H),8.46 (d, 1H), 8.32 (s, 1H), 7.72 (d, 1H), 7.54 (d, 1H), 7.38 (t, 2H),7.20 (t, 1H), 7.18 (s, 1H), 7.04 (d, 2H), 6.73 (d, 1H), 6.51 (s, 1H),4.09 (m, 2H), 2.68 (m, 2H), 2.59 (d, 2H), 1.87 (m, 1H), 1.66 (m, 2H),1.45 (s, 9H), 1.16 (m, 2H).

Using the procedure in Example 457, the following compounds wereprepared from the appropriate thiopropionate and electrophile.

Ex- ample Structure Name ¹H NMR 458

tert-butyl 4-((2-(5-(4- cyanophenylthio)-3- phenoxypyridin-2-ylamino)thiazol-4- yl)methyl)piperidine- 1-carboxylate ¹H NMR (CDCl₃) δ8.85 (s, 1H), 8.24 (s, 1H), 7.47 (d, 2H), 7.42 (t, 2H), 7.24 (t, 1H),7.04-7.13 (m, 5H), 6.50 (s, 1H), 4.08 (m, 2H), 2.69 (m, 2H), 2.59 (d,2H), 1.87 (m, 1H), 1.67 (m, 2H), 1.45 (s, 9H), 1.17 (m, 2H). 459

tert-butyl 3-((2-(3- phenoxy-5- (thieno[3,2-b]pyridin-7-ylthio)pyridin-2- ylamino)thiazol-4- yl)methyl)piperidine-1-carboxylate ¹H NMR (CDCl₃) δ 8.85 (s, 1H), 8.46 (d, 1H), 8.32 (s, 1H),7.72 (d, 1H), 7.54 (d, 1H), 7.38 (t, 2H), 7.20 (t, 1H), 7.18 (s, 1H),7.05 (d, 2H), 6.73 (d, 1H), 6.59 (s, 1H), 4.22 (m, 1H), 4.00 (m, 1H),3.00 (m, 1H), 2.78- 2.91 (m, 2H), 2.21 (m, 1H), 1.72 (m, 2H), 1.58 (m,1H), 1.45 (s, 9H). 460

tert-butyl 3-(5-(3- phenoxy-5- (thieno[3,2-b]pyridin-7-ylthio)pyridin-2- ylamino)-1,2,4- thiadiazol-3- yl)pyrrolidine-1-carboxylate ¹H NMR (CDCl₃) δ 9.21 (s, 1H), 8.49 (d, 1H), 8.37 (s, 1H),7.73 (d, 1H), 7.55 (d, 1H), 7.40 (t, 2H), 7.25 (t, 1H), 7.24 (s, 1H),7.06 (d, 2H), 6.77 (d, 1H), 3.41-3.87 (m, 4H), 2.23-2.35 (m, 2H), 1.46(s, 9H), 1.27 (m, 2H). 461

tert-butyl 3-(2-(3- phenoxy-5- (thieno[3,2-b]pyridin-7-ylthio)pyridin-2- ylamino)thiazol-4- yl)pyrrolidine-1- carboxylate ¹HNMR (CDCl₃) δ 8.87 (s, 1H), 8.46 (d, 1H), 8.32 (s, 1H), 7.72 (d, 1H),7.54 (d, 1H), 7.38 (t, 2H), 7.20 (t, 1H), 7.17 (s, 1H), 7.05 (d, 2H),6.74 (d, 1H), 6.59 (s, 1H), 3.77 (m, 1H), 3.62 (m, 1H), 3.53 (m, 1H),3.41 (m, 2H), 2.25 (m, 1H), 2.11 (m, 1H), 1.47 (s, 7H). 462

tert-butyl 3-(2-(5-(4- cyanophenylthio)-3- phenoxypyridin-2-ylamino)thiazol-4- yl)piperidine-1- carboxylate ¹H NMR (CDCl₃) δ 8.82(s, 1H), 8.24 (s, 1H), 7.47 (d, 2H), 7.42 (t, 2H), 7.22 (t, 1H),7.05-7.13 (m, 5H), 6.58 (s, 1H), 4.21 (m, 1H), 4.00 (m, 1H), 3.00 (m,1H), 2.78-2.90 (m, 2H), 2.10 (m, 1H), 1.72 (m, 2H), 1.58 (m, 1H), 1.47(s, 9H). 463

tert-butyl 3-(5-(5-(4- cyanophenylthio)-3- phenoxypyridin-2-ylamino)-1,2,4- thiadiazol-3- yl)pyrrolidine-1- carboxylate ¹H NMR(CDCl₃) δ 9.19 (s, 1H), 8.30 (s, 1H), 7.49 (d, 2H), 7.43 (t, 2H), 7.26(t, 1H), 7.18 (s, 1H), 7.12 (d, 2H), 7.08 (d, 2H), 3.87 (m, 1H),3.55-3.70 (m, 3H), 3.44 (m, 1H), 2.24-2.35 (m, 2H), 1.47 (s, 9H).

Example 464N-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-yl)-4-(piperidin-4-ylmethyl)thiazol-2-aminedihydrochloride

Added 4N HCl in dioxane (3.0 mL, 12.0 mmol) to a solution of tert-butyl4-((2-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)methyl)piperidine-1-carboxylate(0.790 g, 1.25 mmol) in dichloromethane (4 mL) and methanol (4 mL). Thereaction was stirred at ambient temperature for 3 hours. Concentrated,triturated with hexanes, filtered to afford the title compound (0.745 g,98.5% yield) as a light yellow powder: ¹H NMR (d₆-DMSO) δ 9.13 (m, 1H),8.89 (m, 1H), 8.67 (d, 1H), 8.51 (d, 1H), 8.47 (s, 1H), 7.80 (d, 1H),7.57 (s, 1H), 7.42 (t, 2H), 7.16-7.23 (m, 4H), 6.91 (s, 1H), 3.21 (m,2H), 2.80 (m, 2H), 2.60 (d, 2H), 1.95 (m, 1H), 1.76 (m, 2H), 1.45 (m,2H).

Using the procedure in Example 464, the following compounds wereprepared from the appropriate Boc-protected cyclic amine.

Example Structure Name ¹H NMR 465

N-(3-phenoxy-5- (thieno[3,2- b]pyridin-7- ylthio)pyridin-2-yl)-4-(piperidin-3- yl)thiazol-2-amine dihydrochloride ¹H NMR (d₆-DMSO)δ 9.48 (m, 1H), 9.31 (m, 1H), 8.67 (d, 1H), 8.51 (d, 1H), 8.46 (s, 1H),7.81 (d, 1H), 7.54 (s, 1H), 7.42 (t, 2H), 7.16-7.25 (m, 4H), 6.95 (s,1H), 3.48 (m, 1H), 3.27 (m, 1H), 3.19 (m, 1H), 3.07 (m, 1H), 2.84 (m,1H), 2.08 (m, 1H), 1.82- 1.90 (m, 2H), 1.67 (m, 1H). 466

N-(3-phenoxy-5- (thieno[3,2- b]pyridin-7- ylthio)pyridin-2-yl)-3-(pyrrolidin- 3-yl)-1,2,4- thiadiazol-5-amine dihydrochloride ¹HNMR (d₆-DMSO) δ 9.48 (m, 1H), 8.63 (d, 1H), 8.56 (s, 1H), 8.43 (d, 1H),7.78 (d, 1H), 7.63 (s, 1H), 7.42 (t, 2H), 7.16-7.20 (m, 4H), 3.73 (m,1H), 3.60 (m, 1H), 3.48 (m, 1H), 3.28 (m, 2H), 2.38 (m, 1H), 2.21 (m,1H). 467

N-(3-phenoxy-5- (thieno[3,2- b]pyridin-7- ylthio)pyridin-2-yl)-4-(pyrrolidin- 3-yl)thiazol-2- amine dihydrochloride ¹H NMR(d₆-DMSO) δ 9.61 (m, 1H), 8.67 (d, 1H), 8.51 (d, 1H), 8.46 (s, 1H), 7.80(d, 1H), 7.54 (s, 1H), 7.41 (t, 2H), 7.23 (d, 1H), 7.16-7.20 (m, 3H),3.19- 3.60 (m, 5H), 2.30 (m, 1H), 2.06 (m, 1H).

Example 4684-(5-phenoxy-6-(4-(piperidin-4-ylmethyl)thiazol-2-ylamino)pyridin-3-ylthio)benzonitriledihydrochloride

Added 2,2,2-trifluoroacetic acid (4 mL, 51.9 mmol) to a solution oftert-butyl4-((2-(5-(4-cyanophenylthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)piperidine-1-carboxylate(0.600 g, 1.00 mmol). Stirred at ambient temperature for 3 hours.Partitioned between ethyl acetate and 2N NaOH. Washed the organic layerwith water, brine, dried and concentrated. The residue was dissolved inether (5 mL) and 2N HCl in ether was added. Filtered, washed withhexanes, filtered to afford4-(5-phenoxy-6-(4-(piperidin-4-ylmethyl)thiazol-2-ylamino)pyridin-3-ylthio)benzonitriledihydrochloride (0.454 g, 79.3% yield) as a white powder: ¹H NMR(d-DMSO) δ 8.94 (m, 1H), 8.67 (m, 1H), 8.31 (s, 1H), 7.72 (d, 2H), 7.42(t, 2H), 7.35 (s, 1H), 7.10-7.26 (m, 5H), 7.83 (s, 1H), 3.23 (m, 2H),2.80 (m, 2H), 2.58 (d, 2H), 1.92 (m, 1H), 1.75 (m, 2H), 1.39 (m, 2H).

Using the procedure in Example 468, the following compounds wereprepared from the appropriate Boc-carbamate.

Example Structure Name ¹H NMR 469

4-(5-phenoxy-6- (3-(pyrrolidin-3- yl)-1,2,4- thiadiazol-5-ylamino)pyridin-3- ylthio)benzonitrile dihydrochloride ¹H NMR (d₆-DMSO)δ 9.40 (m, 1H), 8.43 (s, 1H), 7.72 (d, 2H), 7.45 (s, 1H), 7.42 (t, 2H),7.29. (d, 2H), 7.21 (t, 1H), 7.15 (d, 2H), 3.71 (m, 1H), 3.60 (m, 1H),3.48 (m, 1H), 338 (m, 1H), 3.28 (m, 1H), 2.36 (m, 1H), 2.20 (m, 1H). 470

4-(5-phenoxy-6- (3-(piperidin-3- yl)-1,2,4- thiadiazol-5-ylamino)pyridin-3- ylthio)benzonitrile dihydrochloride ¹H NMR (d₆-DMSO)δ 9.23 (m, 1H), 9.10 (m, 1H), 8.30 (s, 1H), 7.72 (d, 2H), 7.43 4, 2H),7.32 (s, 1H), 7.26 (d, 2H), 7.19 (t, 1H), 7.14 (d, 2H), 3.46 (m, 1H),3.26 (m, 1H), 3.15 (m, 1H), 2.98 (m, 1H), 2.85 (m, 1H), 2.07 (m, 1H),1.72-1.90 (m, 2H), 1.65 (m, 1H).

Example 4711-(4-((2-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)methyl)piperidin-1-yl)ethanone

Added acetic anhydride (0.0169 g, 0.165 mmol) to a mixture of3-phenoxy-N-(4-(piperidin-4-ylmethyl)thiazol-2-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-aminedihydrochloride (0.100 g, 0.165 mmol), triethylamine (0.0837 g, 0.827mmol), and THF (5 mL) at 0° C. Warmed to ambient temperature and stirredfor 4 hours. Partitioned between ethyl acetate and 2N NaOH, washed withwater, brine, dried, and concentrated. The residue was dissolved indichloromethane (2 mL) and 1N HCl in ether was added. Diluted inhexanes, and concentrated, added hexanes again and concentrated toafford the title compound ((Mixture of rotamers; 0.092 g, 91.2% yield)as a light yellow powder: ¹H NMR (d₆-DMSO) δ 8.65 (d, 1H); 8.47 (d, 1H),8.46 (s, 1H), 7.77 (d, 1H), 7.41 (s, 1H), 7.41 (d, 2H), 7.15-7.20 (m,4H), 6.84 (s, 1H), 0.95-4.36 (m, 1H), 1.97 (s, 3H).

Using the procedure in Example 471, the following compounds wereprepared from the appropriate amine.

Example Structure Name ¹H NMR 472

1-(3-(2-(3- phenoxy-5- (thieno[3,2- b]pyridin-7- ylthio)pyridin-2-ylamino)thiazol-4- yl)piperidin-1- yl)ethanone (Mixture of rotamers) ¹HNMR (CDCl₃) δ 8.66 (d, 1H), 8.50 (d, 1H), 8.46 (s, 1H), 7.79 (d, 1H),7.55 (s, 1H), 7.41 (t, 2H), 7.23 (d, 1H), 7.14-7.19 (m, 3H), 6.89 (d,1H), 6.58 (bs, 1H), 1.35-4.63 (m, 9H), 2.02 (s, 3H). 473

1-(3-(5-(3- phenoxy-5- (thieno[3,2- b]pyridin-7- ylthio)pyridin-2-ylamino)-1,2,4- thiadiazol-3- yl)pyrrolidin-1- yl)ethanone (Mixture ofrotamers) ¹H NMR (d₆-DMSO) δ 8.59 (d, 1H), 8.54 (s, 1H), 8.33 (d, 1H),7.68 (d, 1H), 7.59 (s, 1H), 7.41 (d, 2H), 7.10-7.20 (m, 5H), 2.10-3.93(m, 7H), 1.96 (s, 3H). 474

1-(3-(2-(3- phenoxy-5- (thieno[3,2- b]pyridin-7- ylthio)pyridin-2-ylamino)thiazol-4- yl)pyrrolidin-1- yl)ethanone (Mixture of rotamers) ¹HNMR (d₆-DMSO) δ 8.47 (d, 1H), 8.32 (s, 1H), 7.73 (d, 1H), 7.54 (d, 1H),7.39 (d, 2H), 7.17-7.24 (m, 3H), 7.06 (d, 2H), 6.75 (d, 1H), 6.62 (s,1H), 6.59 (s, 1H), 2.12- 3.97 (m, 7H), 1.98 (s, 3H). 475

4-(6-(4-(1- acetylpiperidin-3- yl)thiazol-2- ylamino)-5-phenoxypyridin-3- ylthio)benzonitrile (Mixture of rotamers) ¹H NMR(CDCl₃) δ 8.83 (m, 1H), 8.24 (s, 1H), 7.05-7.59 (m, 9H), 6.56 (s, 1H),2.63-4.70 (m, 6H), 2.12 (s, 3H), 1.73-2.20 (m, 3H). 476

4-(6-(3-(1- acetylpyrrolidin-3- yl)-1,2,4- thiadiazol-5- ylamino)-5-phenoxypyridin-3- ylthio)benzonitrile (Mixture of rotamers) ¹H NMR(CDCl₃) δ 9.16 (m, 1H), 8.30 (s, 1H), 7.06-7.53 (m, 9H), 2.29- 3.99 (m,7H), 2.08 (s, 3H). 477

4-(6-(4-((1- acetylpiperidin-4- yl)methyl)thiazol- 2-ylamino)-5-phenoxypyridin-3- ylthio)benzonitrile E20018-397 ¹H NMR (d₆-DMSO) δ11.07 (s, 1H), 8.23 (s, 1H), 7.66 (d, 2H), 7.04-7.37 (m, 8H), 6.65 (s,1H), 4.27 (m, 1H), 3.71 (m, 1H), 2.89 (m, 1H), 2.45 (d, 2H), 2.41 (m,1H), 1.91 (s, 3H), 1.85 (m, 1H), 1.54 (m, 2H), 0.89-1.10 (m, 2H).

Example 4781-(4-(2-(5-(2-chloropyridin-4-ylthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone

Using the procedure in Example 16, the title compound was prepared: ¹HNMR (CDCl₃) δ 8.24 (s, 1H), 8.13 (d, 1H), 7.42 (t, 2H), 7.24 (t, 1H),7.07-7.12 (m, 2H), 6.82-6.86 (m, 2H), 6.52 (s, 1H), 4.72 (m, 1H), 3.91(m, 1H), 3.19 (m, 1H), 2.88 (m, 1H), 2.70 (m, 1H), 2.12 (m, 1H),2.03-2.11 (m, 2H), 1.60-1.71 (m, 2H).

Example A In Vitro Glucokinase Assays

The in vitro efficacy of glucokinase activators of the present inventionwas assessed in two separate assays: an EC₅₀ assay to evaluate thepotency of each compound at a fixed, physiologically relevantconcentration of glucose, and a glucose S_(0.5) assay at a fixed, nearsaturating (if possible) concentration of compound to evaluate itseffect on the V_(m) and S_(0.5) for glucose. For each of these assays,glucokinase activity was estimated by monitoring the increase inabsorbance at 340 nm in a coupled assay system containing NAD⁺ andglucose 6-phosphate dehydrogenase. Assays were conducted at 30° C. usinga thermostatically controlled absorbance plate reader (Spectramax 340PC,Molecular Devices Corp.) and clear, 96-well, flat bottom, polystyreneplates (Costar 3695, Corning). Each 50-μL assay mixture contained 10 mMK⁺MOPS, pH 7.2, 2 mM MgCl₂, 50 mM KCl, 0.01% Triton X-100, 2% DMSO, 1 mMDTT, 1 mM ATP, 1 mM NAD⁺, 5 U/mL glucose 6-phosphate dehydrogenase,approximately 5 nM human glucokinase and (depending on the assay)varying concentrations of glucose and test compound. The absorbance at340 nm was monitored kinetically over a period of 5 minutes (10s/cycle), and rates were estimated from the slopes of linear fits to theraw data.

Glucokinase EC₅₀ Assay:

For this assay, the glucose concentration was fixed at 5 mM, while thecontrol or test compound was varied over a 10-point, 3-fold dilutionseries and typically ranged from a high dose of 50 μM to a low dose ofapproximately 2.5 nM. A standard, four-parameter logistic model(Equation 1) was fit to the raw data (rate versus concentration ofcompound):

$\begin{matrix}{y = {A + \frac{B - A}{1 + \left\lbrack \frac{C}{x} \right\rbrack^{D}}}} & (1)\end{matrix}$

where x is the concentration of compound, y is the estimated rate, A andB are the lower and upper asymptotes, respectively, C is the EC₅₀ and Dis the Hill slope. The EC₅₀ is defined as the midpoint or inflectionpoint between the upper and lower asymptotes.

The compounds exemplified herein have been found to have an EC₅₀ in therange of 6 and 50,000 nM in the above described assay. Certain compoundsexemplified herein have been found to have an EC₅₀ in the range of 3 nMand 5000 nM.

Glucose S_(0.5) Assay:

For this assay, the concentration of control or test compound was fixedat or near a saturating concentration, if possible, typically 50 μM,while the glucose concentration was varied over a 10-point, 2-folddilution series ranging from 80 to approximately 0.16 mM. The samefour-parameter logistic model used for the EC₅₀ assay (Equation 1) wasemployed to estimate the relevant kinetic parameters. In this assay, thedefinitions for the variables and parameters are similar except that xrepresents the concentration of glucose, B is the rate at saturatingglucose (V_(m)), C is the S_(0.5) for glucose (the concentration ofglucose at V_(m)/2) and D is the Hill Coefficient.

The compounds exemplified herein have been found to have an S_(0.5) ofbetween 0.3 and 5 mM in the above described assay.

The foregoing description is considered as illustrative only of theprinciples of the invention. Further, since numerous modifications andchanges will be readily apparent to those skilled in the art, it is notdesired to limit the invention to the exact construction and processshown as described above. Accordingly, all suitable modifications andequivalents may be resorted to falling within the scope of the inventionas defined by the claims that follow.

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groupsthereof.

The invention claimed is:
 1. A method of treating a disease or conditionin a mammal resulting from underactivity of glucokinase or which can betreated by activating glucokinase, comprising administering to saidmammal an effective amount of a compound selected from the Formula

and salts thereof, wherein: L is O, S, C(═O) or CHR¹⁴; Y is CR⁴; Z isCR³; G is CR¹¹; R¹ is a heteroaryl ring represented by the formula

D¹ is S; D² is N or CR¹²; D³ is S, O or CR¹³; R² is aryl, heteroaryl,saturated or partially unsaturated cycloalkyl, or saturated or partiallyunsaturated heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl andheterocyclyl are monocyclic or bicyclic and are optionally substitutedwith one or more groups independently selected from C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, saturated and partially unsaturated C₃-C₆cycloalkyl, saturated and partially unsaturated C₁-C₆ heterocyclyl,aryl, heteroaryl, F, Cl, Br, I, CF₃, CN, NO₂, OR⁶, C(═O)R⁶, C(═O)OR⁶,OC(═O)R⁶, O(CH₂)_(n)C(═O)OR⁶, O(CH₂)_(n)C(═O)NR⁶R⁷, C(═O)NR⁶R⁷, NR⁶R⁷,NR⁶C(═O)R⁷, SR⁶, S(O)R⁶, and S(O)₂R⁶, and wherein said alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with one or more groups independently selected from oxo,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturated and partiallyunsaturated C₃-C₆V_(n)-cycloalkyl, saturated and partially unsaturatedC₁-C₆V_(n)-heterocyclyl, V_(n)-aryl, V_(n)-heteroaryl, V_(n)—F,V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—CF₃, V_(n)—CN, V_(n)—OR⁸,V_(n)—C(═O)R⁸, V_(n)—C(═O)OR⁸, V_(n)—OC(═O)R⁸, V_(n)—C(═O)NR⁸R⁹,V_(n)—NR⁸R⁹, V_(n)—NR⁸C(═O)R⁹, V_(n)—SR⁸, V_(n)—S(O)R⁸, andV_(n)—S(O)₂R⁸; R³ is H, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,saturated or partially unsaturated C₃-C₁₂ cycloalkyl, saturated orpartially unsaturated C₁-C₁₂ heterocyclyl, aryl, heteroaryl, F, Cl, Br,I, CN, OR⁶, C(═O)R⁶, C(═O)OR⁶, OC(═O)R⁶, C(═O)NR⁶R⁷, OC(═O)NR⁶R⁷,OC(═S)NR⁶R⁷, NR⁶R⁷, NR⁶C(═O)R⁷, SR⁶, S(O)R⁶, S(O)₂R⁶ or S(O)₂NR⁶R⁷,wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl andheteroaryl are optionally substituted with one or more groupsindependently selected from oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, saturated and partially unsaturated C₃-C₆ cycloalkyl, saturatedand partially unsaturated C₁-C₆ heterocyclyl, V_(n)-aryl,V_(n)-heteroaryl, V_(n)—F, V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—CF₃,V_(n)—CN, V_(n)—OR⁸, V_(n)—C(═O)R⁸, V_(n)—C(═O)OR⁸, V_(n)—OC(═O)R⁸,V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹, V_(n)—NR⁸C(═O)R⁹, V_(n)—SR⁸,V_(n)—S(O)R⁸, V_(n)—S(O)₂R⁸ and V_(n)—S(O)₂NR⁸R⁹; R⁴ is H; R⁶ and R⁷ areindependently H, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, saturatedor partially unsaturated C₃-C₁₂ cycloalkyl, saturated or partiallyunsaturated C₁-C₁₂ heterocyclyl, V_(n)-aryl, or V_(n)-heteroaryl,wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl andheteroaryl portions are optionally substituted with one or more groupsindependently selected from oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, saturated and partially unsaturated C₃-C₆ cycloalkyl, saturatedand partially unsaturated C₁-C₆ heterocyclyl [optionally substitutedwith C(O)O(1-6C alkyl), (1-6C)alkyl or (1-6C alkyl)OH], V_(n)-aryl,V_(n)-heteroaryl, V_(n)—F, V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—CF₃,V_(n)—CN, V_(n)—OR⁸, V_(n)—C(═O)R⁸, V_(n)—C(═O)OR⁸, V_(n)—OC(═O)R⁸,V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹, V_(n)—NR⁸C(═O)R⁹, V_(n)—SR⁸,V_(n)—S(O)R⁸, V_(n)—S(O)₂R⁸, V_(n)—S(O)₂NR⁸R⁹, and (C₁-C₆ alkyl)OH; orR⁶ and R⁷ together with the atoms to which they are attached form asaturated or partially unsaturated heterocyclic ring, wherein saidheterocyclic ring optionally comprises one or more additional ringheteroatoms independently selected from N, O or S, wherein saidheterocyclic ring is optionally substituted with one or more groupsindependently selected from oxo, V_(n)—F, V_(n)—Cl, V_(n)—Br, V_(n)—I,V_(n)—OR⁸, V_(n)—C(═O)OR⁸, V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹,V_(n)—NR⁸C(═O)R⁹, V_(n)—NR⁸C(═O)NR⁹R¹⁰, C₁-C₆ alkyl, C₂-C₆ alkenyl, andC₂-C₆ alkynyl; R⁸, R⁹ and R¹⁰ are independently H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, saturated and partially unsaturated C₃-C₆cycloalkyl, saturated and partially unsaturated C₁-C₆ heterocyclyl, arylor heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl and heteroaryl are optionally substituted with one ormore groups independently selected from oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, saturated and partially unsaturated C₃-C₆ cycloalkyl,saturated and partially unsaturated C₁-C₆ heterocyclyl, V_(n)-aryl,V_(n)-heteroaryl, V_(n)—F, V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—OR^(a),V_(n)—NR^(a)R^(b), V_(n)—C(═O)OR^(a), V_(n)—C(═O)NR^(a)R^(b), andV_(n)—NR^(a)C(═O)R^(b), or R⁸ and R⁹ together with the atoms to whichthey are attached form a saturated or partially unsaturated heterocyclicring, wherein said heterocyclic ring optionally comprises one or moreadditional ring heteroatoms independently selected from N, O or S,wherein said heterocyclic ring is optionally substituted with one ormore groups independently selected from oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, V_(n)—F, V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—OR^(a), andV_(n)—CN, or R⁹ and R¹⁰ together with the atoms to which they areattached form a saturated or partially unsaturated heterocyclic ring,wherein said heterocyclic ring optionally comprises one or moreadditional ring heteroatoms independently selected from N, O or S,wherein said heterocyclic ring is optionally substituted with one ormore groups independently selected from oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, V_(n)—F, V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—OR^(a), andV_(n)—CN; R¹¹ is H; R¹² and R¹³ are independently H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, saturated and partially unsaturated C₃-C₆cycloalkyl, saturated and partially unsaturated C₁-C₆ heterocyclyl,CH₂-heterocyclyl, aryl, heteroaryl, (1-3C alkyl)heteroaryl,(CH₂)_(n)(CR^(x)R^(y))C(O)NR⁸R⁹, (CH₂)_(n)(CR^(x)R^(y))C(O)NH—N═CHNR⁸R⁹,F, Cl, Br, I, CF₃, CN, OR⁶, C(═O)R⁶, C(═O)OR⁶, OC(═O)R⁶, C(═O)NR⁶R⁷,NR⁶R⁷, NR⁶C(═O)R⁷, SR⁶, S(O)R⁶, S(O)₂R⁶, wherein said alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionallysubstituted with one or more groups independently selected from oxo,V_(n)—F, V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—CF₃, V_(n)—CN, V_(n)—OR⁸,V_(n)—C(═O)OR⁸, V_(n)—OC(═O)R⁸, V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹,V_(n)—NR⁸C(═O)R⁹, C(O)(C₁-C₆ alkyl), C(O)-heterocycle [optionallysubstituted with O—(C₁-C₆ alkyl], SR^(a), SO₂R^(f), SO₂NR^(c)R^(e),C(O)(C₁-C₆ alkyl)NR^(c)R^(d), C(O)(C₁-C₆ alkyl)OR^(c), C(O)CH₂C(O)(C₁-C₆alkyl), C(═O)CHR^(g)NHC(═O)(C₁-C₆ alkyl), C(═O)CH₂C(═O)(C₁-C₆ alkyl),C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturated and partiallyunsaturated C₃-C₆ cycloalkyl, saturated and partially unsaturated C₁-C₆heterocyclyl, V_(n)-aryl, and V_(n)-heteroaryl, wherein saidheterocyclyl is optionally substituted with one or more oxo, or R¹² andR¹³ together with the atoms to which they are attached form a saturated,partially unsaturated or aromatic carbocyclic or heterocyclic ring,wherein said carbocyclic and heterocyclic rings are optionallysubstituted with one or more groups independently selected from C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturated and partially unsaturatedC₃-C₆ cycloalkyl, saturated and partially unsaturated C₁-C₆heterocyclyl, aryl, heteroaryl, oxo, F, Cl, Br, I, CF₃, CN, OR⁶,C(═O)R⁶, C(═O)OR⁶, OC(═O)R⁶, C(═O)NR⁶R⁷, NR⁶R⁷, NR⁶C(═O)R⁷, SR⁶, S(O)R⁶,S(O)₂R⁶ and SO₂NR⁶R⁷, wherein said alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl and heteroaryl are optionally substituted with one ormore groups independently selected from oxo, V_(n)—F, V_(n)—Cl,V_(n)—Br, V_(n)—I, V_(n)—CF₃, V_(n)—CN, V_(n)—OR⁸, V_(n)—C(═O)OR⁸,V_(n)—OC(═O)R⁸, V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹, V_(n)—NR⁸C(═O)R⁹, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturated and partially unsaturatedC₃-C₆ cycloalkyl, saturated and partially unsaturated C₁-C₆heterocyclyl, V_(n)-aryl, and V_(n)-heteroaryl; R¹⁴ is H, methyl, ethylor OH; R^(a) and R^(b) are independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, saturated and partially unsaturated V_(n)—C₃-C₆cycloalkyl, saturated and partially unsaturated V_(n)—C₁-C₆heterocyclyl, V_(n)-aryl, or V_(n)-heteroaryl, wherein said alkyl,alkenyl, alkynyl, saturated or partially unsaturated V_(n)-cycloalkyl,saturated or partially unsaturated V_(n)-heterocyclyl, V_(n)-aryl, andV_(n)-heteroaryl are optionally substituted with one or more OH; eachR^(c), R^(e) and R^(g) is independently H or C₁-C₆ alkyl; R^(d) is H,C₁-C₆ alkyl or C(O)O(C₁-C₆ alkyl); R^(f) is C₁-C₆ alkyl or (C₁-C₆alkyl)NH₂; R^(x) is H or C₁-C₆ alkyl; R^(y) is H, C₁-C₆ alkyl, or—O(C₁-C₆ alkyl); V is alkylene having from 1 to 12 carbons, oralkenylene or alkynylene each having from 2 to 12 carbons, wherein saidalkylene, alkenylene, or alkynylene are optionally substituted with oneor more groups independently selected from C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, saturated and partially unsaturated C₃-C₆ cycloalkyl,saturated and partially unsaturated C₁-C₆ heterocyclyl, aryl,heteroaryl, F, Cl, Br, I, CF₃, cyano, OR⁸, C(═O)OR⁸, OC(═O)R⁸,C(═O)NR⁸R⁹, NR⁸R⁹, (C₁-C₆ alkyl)NR^(c)R^(e), and NR⁸C(═O)R⁹; and n is 0or
 1. 2. The compound of claim 1, wherein: R⁶ and R⁷ are optionallysubstituted with one or more groups independently selected from oxo,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturated and partiallyunsaturated C₃-C₆ cycloalkyl, saturated and partially unsaturated C₁-C₆heterocyclyl, V_(n)-aryl, V_(n)-heteroaryl, V_(n)—F, V_(n)—Cl, V_(n)—Br,V_(n)—I, V_(n)—CF₃, V_(n)—CN, V_(n)—OR⁸, V_(n)—C(═O)R⁸, V_(n)—C(═O)OR⁸,V_(n)—OC(═O)R⁸, V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹, V_(n)—NR⁸C(═O)R⁹,V_(n)—SR⁸, V_(n)—S(O)R⁸, V_(n)—S(O)₂R⁸, and V_(n)—S(O)₂NR⁸R⁹, and R¹²and R¹³ are independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,saturated and partially unsaturated C₃-C₆ cycloalkyl, saturated andpartially unsaturated C₁-C₆ heterocyclyl, aryl, heteroaryl, F, Cl, Br,I, CF₃, CN, OR⁶, C(═O)R⁶, C(═O)OR⁶, OC(═O)R⁶, C(═O)NR⁶R⁷, NR⁶R⁷,NR⁶C(═O)R⁷, SR⁶, S(O)R⁶ or S(O)₂R⁶, wherein said alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionallysubstituted with one or more groups independently selected from oxo,V_(n)—F, V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—CF₃, V_(n)—CN, V_(n)—OR⁸,V_(n)—C(═O)OR⁸, V_(n)—OC(═O)R⁸, V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹,V_(n)—NR⁸C(═O)R⁹, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturatedand partially unsaturated C₃-C₆ cycloalkyl, saturated and partiallyunsaturated C₁-C₆ heterocyclyl, V_(n)-aryl, and V_(n)-heteroaryl,wherein said heterocyclyl is optionally substituted with one or moreoxo, or R¹² and R¹³ together with the atoms to which they are attachedform a saturated, partially unsaturated or aromatic carbocyclic orheterocyclic ring, wherein said carbocyclic and heterocyclic rings areoptionally substituted with one or more groups independently selectedfrom C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturated and partiallyunsaturated C₃-C₆ cycloalkyl, saturated and partially unsaturated C₁-C₆heterocyclyl, aryl, heteroaryl, oxo, F, Cl, Br, I, CF₃, CN, OR⁶,C(═O)R⁶, C(═O)OR⁶, OC(═O)R⁶, C(═O)NR⁶R⁷, NR⁶R⁷, NR⁶C(═O)R⁷, SR⁶, S(O)R⁶,S(O)₂R⁶ and SO₂NR⁶R⁷, wherein said alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl and heteroaryl are optionally substituted with one ormore groups independently selected from oxo, V_(n)—F, V_(n)—Cl,V_(n)—Br, V_(n)—I, V_(n)—CF₃, V_(n)—CN, V_(n)—OR⁸, V_(n)—C(═O)OR⁸,V_(n)—OC(═O)R⁸, V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹, V_(n)—NR⁸C(═O)R⁹, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturated and partially unsaturatedC₃-C₆ cycloalkyl, saturated and partially unsaturated C₁-C₆heterocyclyl, V_(n)-aryl, and V_(n)-heteroaryl.
 3. The compound of claim1 wherein R¹ is selected from:

wherein R²⁰ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturatedand partially unsaturated C₃-C₆ cycloalkyl, saturated and partiallyunsaturated C₁-C₆ heterocyclyl, aryl, heteroaryl, oxo, F, Cl, Br, I,CF₃, CN, OR⁶, C(═O)R⁶, C(═O)OR⁶, OC(═O)R⁶, C(═O)NR⁶R⁷, NR⁶R⁷,NR⁶C(═O)R⁷, SR⁶, S(O)R⁶, S(O)₂R⁶ and SO₂NR⁶R⁷, wherein said alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl areoptionally substituted with one or more groups independently selectedfrom oxo, V_(n)—F, V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—CF₃, V_(n)—CN,V_(n)—OR, V_(n)—C(═O)OR⁸, V_(n)—OC(═O)R⁸, V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹,V_(n)—NR⁸C(═O)R⁹, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturatedand partially unsaturated C₃-C₆ cycloalkyl, saturated and partiallyunsaturated C₁-C₆ heterocyclyl, V_(n)-aryl, and V_(n)-heteroaryl.
 4. Thecompound of claim 3, wherein R²⁰ is H.
 5. The compound of claim 1,having the Formula Ia

wherein: L is O, S, or CH₂; Y is CH: D² is N or CR¹²; R² is aryl,heteroaryl, saturated or partially unsaturated cycloalkyl, or saturatedor partially unsaturated heterocyclyl, wherein said aryl, heteroaryl,cycloalkyl and heterocyclyl are monocyclic or bicyclic and areoptionally substituted with one or more groups independently selectedfrom C₁-C₆ alkyl, (C₁-C₆ alkyl)OH, C₁-C₆ heterocyclyl, F, Cl, Br, CF₃,CN, NO₂, OR⁶, C(═O)R⁶, C(═O)OR⁶, C(═O)NR⁶R⁷, S(O)₂R⁶, C(O)CH₂NH₂, andC(O)CH₂NR⁸R⁹, R³ is H, C₁-C₁₂ alkyl, aryl, heteroaryl, F, Cl, Br, OR⁶,or SR⁶, wherein said alkyl, aryl and heteroaryl are optionallysubstituted with one or more groups independently selected from C₁-C₆alkyl, C₂-C₆ alkenyl, saturated and partially unsaturated C₁-C₆heterocyclyl, V_(n)—OR⁸, V_(n)—C(═O)OR⁸, and V_(n)—NR⁸R⁹; R⁶ and R⁷ areindependently H, C₁-C₁₂ alkyl, saturated or partially unsaturated C₃-C₁₂cycloalkyl, saturated or partially unsaturated C₁-C₁₂ heterocyclyl,V_(n)-aryl, or V_(n)-heteroaryl, wherein said alkyl, cycloalkyl,heterocyclyl, aryl and heteroaryl portions are optionally substitutedwith one or more groups independently selected from C₁-C₆ alkyl,saturated and partially unsaturated C₁-C₆ heterocyclyl [optionallysubstituted with C(O)O(C₁-C₆ alkyl) or (C₁-C₆ alkyl)OH], aryl,heteroaryl, CF₃, F, Cl, Br, I, CN, OR⁸, C(═O)R⁸, C(═O)OR⁸, C(═O)NR⁸R⁹,NR⁸R⁹, NR⁸C(═O)R⁹ or (C₁-C₆ alkyl)OH, or R⁶ and R⁷ together with theatoms to which they are attached form a saturated or partiallyunsaturated heterocyclic ring, wherein said heterocyclic ring optionallycomprises one or more additional ring heteroatoms independently selectedfrom N, O or S; R⁸, R⁹ and R¹⁰ are independently H, C₁-C₆ alkyl, orsaturated and partially unsaturated C₁-C₆ heterocyclyl, wherein saidalkyl and heterocyclyl are optionally substituted with one or moregroups independently selected from C₁-C₆ alkyl, saturated and partiallyunsaturated C₁-C₆ heterocyclyl, OR^(a), NR^(a)R^(b), C(═O)OR^(a) andC(═O)NR^(a)R^(b), or R⁸ and R⁹ together with the atoms to which they areattached form a saturated or partially unsaturated heterocyclic ring; orR⁹ and R¹⁰ together with the atoms to which they are attached form asaturated or partially unsaturated heterocyclic ring; R¹² is H or C₁-C₆alkyl; R¹³ is H, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, saturatedand partially unsaturated C₃-C₆ cycloalkyl, saturated and partiallyunsaturated C₁-C₆ heterocyclyl, CH₂-heterocyclyl, aryl, heteroaryl,(1-3C alkyl)heteroaryl, or (CH₂)_(n)(CR^(x)R^(y))C(O)NR⁸R⁹, wherein saidalkyl, alkenyl, alkynyl, cycloalkyl, CH₂-heterocyclyl, heterocyclyl,aryl, heteroaryl and (1-3C alkyl)heteroaryl are optionally substitutedwith one or more groups independently selected from oxo, F, Cl, CF₃, CN,OR⁸, C(═O)OR⁸, C(═O)NR⁸R⁹, NR⁸R⁹, C(O)(C₁-C₆ alkyl), C(O)-heterocycle[optionally substituted with O—(C₁-C₆ alkyl) or oxo], SR^(a), SO₂R^(f),SO₂NR^(c)R^(e), C(O)(C₁-C₆ alkyl)NR^(c)R^(d), C(O)(C₁-C₆ alkyl)OR^(c),C(O)CH₂C(O)(C₁-C₆ alkyl), C₁-C₆ alkyl, saturated and partiallyunsaturated C₁-C₆ heterocycle (optionally substituted with oxo) andaryl; or R¹² and R¹³ together with the atoms to which they are attachedform a heteroaryl ring; R^(a) and R^(b) are independently H, C₁-C₆alkyl, or saturated or partially unsaturated C₁-C₆ heterocyclyl; eachR^(c), R^(e) and R^(g) is independently H or C₁-C₆ alkyl; R^(d) is H,C₁-C₆ alkyl or C(O)O(C₁-C₆ alkyl); R^(f) is C₁-C₆ alkyl or (C₁-C₆alkyl)NH₂; V is alkylene having from 1 to 4 carbons, or alkenylenehaving from 2 to 4 carbons, wherein said alkylene and alkenylene areoptionally substituted with C₁-C₆ alkyl, O(C₁-C₆ alkyl), or (C₁-C₆alkyl)NR^(c)R^(e); and n is 0 or
 1. 6. The compound of claim 1, whereinR¹² is H.
 7. The compound of claim 1, wherein R¹³ is selected from H,C₁-C₆ alkyl, chloro(C₁-C₆ alkyl), CF₃, (3-6C)cycloalkyl, (C₁-C₆alkyl)CN, (C₁-C₆ alkyl)CO₂R⁸, (C₁-C₆ alkyl)SR^(a), (C₁-C₆alkyl)SO₂R^(f), (C₁-C₆ alkyl)aryl, (C₁-C₆ alkyl)OR⁸, (C₁-C₆ alkyl)NR⁸R⁹,(CH₂)_(n)(CR^(x)R^(y))C(O)NR⁸R⁹, (CH₂)_(n)(CR^(x)R^(y))C(O)NH—N═CHNR⁸R⁹,(C₁-C₆ alkyl)C(O)-heterocyclyl, aryl, heteroaryl, (C₁-C₃ alkyl)hetAr¹,CH₂(CR^(x)R^(y))C(O)OR⁸, CH₂(CR^(x)R^(y))C(O)heterocyclyl [optionallysubstituted with one or two groups selected from O—(C₁-C₆ alkyl) andoxo], CH₂CH(CO₂H)—CH₂CH₂NHR⁸, hetCyc¹ and CH₂hetCyc², wherein: R^(x) andR^(y) are independently H, methyl or OMe, n is 0 or 1, hetCyc¹ is asaturated and partially unsaturated C₁-C₆ heterocyclic ring optionallysubstituted with one or more groups independently selected from C₁-C₆alkyl, C(O)(C₁-C₆ alkyl), (C₁-C₆ alkyl)OH, C(O)O(C₁-C₆ alkyl),C(O)(C₁-C₆ alkyl)NR^(e)R^(d), C(O)(C₁-C₆ alkyl)OR^(c), C(O)CH₂C(O)(C₁-C₆alkyl), C(O)NR⁸R⁹, SO₂NR^(c)R^(e), SO₂R^(f), C(═O)CHR^(g)NHC(═O)(C₁-C₆alkyl) and C(═O)CH₂C(═O)(C₁-C₆ alkyl), hetCyc² is a heterocyclic ringoptionally substituted with one or more groups independently selectedfrom C₁-C₆ alkyl, C(O)(C₁-C₆ alkyl), C(O)O(C₁-C₆ alkyl), and oxo, andhetAr¹ is a heteroaryl ring optionally substituted with C₁-C₆ alkyl, OHor CF₃.
 8. The compound of claim 1, wherein R² is: (i) phenyl optionallysubstituted with one or more groups independently selected from F, Cl,Br, CN, CF₃, C₁-C₆ alkyl, NO₂, SO₂ (C₁-C₆ alkyl), OH, O(C₁-C₆ alkyl),CO₂H, CO₂ (C₁-C₆ alkyl), C(O) saturated and partially unsaturated C₁-C₁₂heterocyclyl [optionally substituted with C₁-C₆ alkyl], saturated andpartially unsaturated C₁-C₆ heterocyclyl and C(O)NR⁶R⁷; (ii) a 5-6membered heteroaryl ring having 1-2 nitrogen atoms; (iii) a 9-10membered bicyclic heteroaryl ring having a having 1 to 2 ring atomsindependently selected from N and S; (iv) a 5 membered saturated andpartially unsaturated heterocyclic ring having at least one nitrogenatom, wherein the heterocyclic ring is optionally substituted withCO₂—(C₁-C₆ alkyl), C(O)NH(C₁-C₆ alkyl), C(O)CH₂N(C₁-C₆ alkyl)₂,C(O)(C₁-C₆ alkyl)CO₂H, or SO₂-(heteroaryl); or (v) a 5-6 memberedsaturated or partially unsaturated cycloalkyl ring.
 9. The compound ofclaim 1, wherein R³ is H, Br, Cl, SR⁶, OR⁶, aryl, heteroaryl, or C₁-C₆alkyl, wherein said aryl is optionally substituted with Cl and saidalkyl is optionally substituted with C(O)OR⁸, NR⁸R⁹, or OR⁸.
 10. Thecompound of claim 1, wherein R³ is: (i) S—V_(n)-aryl wherein n is 0, andaryl is phenyl optionally substituted with one or two groupsindependently selected from Cl, OH, CN, CF₃, CO₂H, O(C₁-C₆ alkyl),O(C₁-C₆ alkyl)CO₂H, O(C₁-C₆ alkyl)NR^(a)R^(b), or O(C₁-C₆ alkyl)-saturated and partially unsaturated C₁-C₆ heterocycle; (ii) S—V_(n)-arylwherein n is 1, V is alkylene optionally substituted withCH₂CH₂NR^(c)R^(e), and aryl is phenyl optionally substituted with F, Cl,or O(C₁-C₆ alkyl); (iii) S—V_(n)-heteroaryl wherein n is 1, V is C₁-C₆alkylene optionally substituted with C₁-C₆ alkyl, and heteroaryl is a5-6 membered ring having 1-2 atoms independently selected from N, S andO; (iv) S—V_(n)-heteroaryl wherein n is 1, V is C₁-C₆ alkylene, andheteroaryl is a 10-membered bicyclic heteroaryl having at least onenitrogen; (v) SR⁶ wherein R⁶ is V_(n)-heteroaryl, n is 0, and theheteroaryl group is a 9-10 membered bicyclic heteroaromatic ring having2-3 atoms independently selected from N, S and O, and optionallysubstituted with one or two groups independently selected from I, Br,C₁-C₆ alkyl and CO₂H; (vi) S—V_(n)-heteroaryl wherein n is 0, andheteroaryl is a 5-6 membered ring having 1-4 atoms independentlyselected from N and S and optionally substituted with one or two groupsindependently selected from Cl, CN, C₁-C₆ alkyl, O—(C₁-C₆ alkyl), (C₁-C₆alkyl)NR⁸R⁹, (C₁-C₆ alkyl)CN, C(═O)O(C₁-C₆ alkyl), and CF₃; (vii)S—CHR^(6a)R^(6b) wherein R^(6a) is piperidinyl (optionally substitutedwith C₁-C₆ alkyl, CO₂—(C₁-C₆ alkyl) or (C₁-C₆ alkyl)OH) or a structurehaving the formula

 and R^(6b) is pyridyl, pyrimidyl, C(O)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)OH,C(O)NH(C₁-C₆ alkyl), C(O)NH-heterocycle, or (C₁-C₆ alkyl); (viii) S—saturated and partially unsaturated C₃-C₁₂ cycloalkyl, (ix) S— saturatedand partially unsaturated C₁-C₁₂ heterocyclyl which is optionallysubstituted with oxo; (x) S—(C₁-C₆ alkyl)C(O)OR⁸; (xi) S—CH₂C(O)—saturated and partially unsaturated C₁-C₆ heterocycle, S—CH₂C(O)—NR⁸(C₁-C₆ alkyl)NR^(a)R^(b), S—CH₂C(O)—NR(C₁-C₆ alkyl)- saturated andpartially unsaturated C₁-C₆ heterocycle, or S—(C₁-C₆ alkyl)NR⁸R⁹; (xii)OH, O—(C₁-C₆ alkyl), O—(C₁-C₆ alkyl)aryl, O—(C₁-C₆ alkyl)-saturated andpartially unsaturated C₁-C₆ heterocycle, O—(C₁-C₆ alkyl)NR⁸R⁹, orO-phenyl which is optionally substituted with Br; (xiii) phenyloptionally substituted with Cl; (xiv) a 6-membered heteroaryl having atleast one nitrogen; (xv) C₁-C₆ alkyl, (C₁-C₆ alkyl)-saturated andpartially unsaturated C₁-C₆ heterocycle, (C₁-C₆ alkyl)heteroaryl, (C₁-C₆alkyl)OH, (C₁-C₆ alkyl)CO₂R⁸, (C₁-C₆ alkyl)CO₂ (C₁-C₆ alkyl), (C₁-C₆alkyl)NR⁸R⁹, or (C₂-C₆ alkenyl)CO₂R⁸; or (xvi) Br, Cl or H.
 11. A methodof activating glucokinase in a mammal, comprising administering to saidmammal an effective amount of a compound selected from the Formula

and salts thereof, wherein: L is O, S, C(═O) or CHR¹⁴; Y is CR⁴; Z isCR³; G is CR¹¹; R¹ is a heteroaryl ring represented by the formula

D¹ is S; D² is N or CR¹²; D³ is S, O or CR¹³; R² is aryl, heteroaryl,saturated or partially unsaturated cycloalkyl, or saturated or partiallyunsaturated heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl andheterocyclyl are monocyclic or bicyclic and are optionally substitutedwith one or more groups independently selected from C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, saturated and partially unsaturated C₃-C₆cycloalkyl, saturated and partially unsaturated C₁-C₆ heterocyclyl,aryl, heteroaryl, F, Cl, Br, I, CF₃, CN, NO₂, OR⁶, C(═O)R⁶, C(═O)OR⁶,OC(═O)R⁶, O(CH₂)_(n)C(═O)OR⁶, O(CH₂)_(n)C(═O)NR⁶R⁷, C(═O)NR⁶R⁷, NR⁶R⁷,NR⁶C(═O)R⁷, SR⁶, S(O)R⁶, and S(O)₂R⁶, and wherein said alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with one or more groups independently selected from oxo,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturated and partiallyunsaturated C₃-C₆V_(n)-cycloalkyl, saturated and partially unsaturatedC₁-C₆V_(n)-heterocyclyl, V_(n)-aryl, V_(n)-heteroaryl, V_(n)—F,V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—CF₃, V_(n)—CN, V_(n)—OR⁸,V_(n)—C(═O)R⁸, V_(n)—C(═O)OR⁸, V_(n)—OC(═O)R⁸, V_(n)—C(═O)NR⁸R⁹,V_(n)—NR⁸R⁹, V_(n)—NR⁸C(═O)R⁹, V_(n)—SR⁸, V_(n)—S(O)R⁸, andV_(n)—S(O)₂R⁸; R³ is H, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,saturated or partially unsaturated C₃-C₁₂ cycloalkyl, saturated orpartially unsaturated C₁-C₁₂ heterocyclyl, aryl, heteroaryl, F, Cl, Br,I, CN, OR⁶, C(═O)R⁶, C(═O)OR⁶, OC(═O)R⁶, C(═O)NR⁶R⁷, OC(═O)NR⁶R⁷,OC(═S)NR⁶R⁷, NR⁶R⁷, NR⁶C(═O)R⁷, SR⁶, S(O)R⁶, S(O)₂R⁶ or S(O)₂NR⁶R⁷,wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl andheteroaryl are optionally substituted with one or more groupsindependently selected from oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, saturated and partially unsaturated C₃-C₆ cycloalkyl, saturatedand partially unsaturated C₁-C₆ heterocyclyl, V_(n)-aryl,V_(n)-heteroaryl, V_(n)—F, V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—CF₃,V_(n)—CN, V_(n)—OR⁸, V_(n)—C(═O)R⁸, V_(n)—C(═O)OR⁸, V_(n)—OC(═O)R⁸,V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹, V_(n)—NR⁸C(═O)R⁹, V_(n)—SR⁸,V_(n)—S(O)R⁸, V_(n)—S(O)₂R⁸ and V_(n)—S(O)₂NR⁸R⁹; R⁴ is H; R⁶ and R⁷ areindependently H, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, saturatedor partially unsaturated C₃-C₁₂ cycloalkyl, saturated or partiallyunsaturated C₁-C₁₂ heterocyclyl, V_(n)-aryl, or V_(n)-heteroaryl,wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl andheteroaryl portions are optionally substituted with one or more groupsindependently selected from oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, saturated and partially unsaturated C₃-C₆ cycloalkyl, saturatedand partially unsaturated C₁-C₆ heterocyclyl [optionally substitutedwith C(O)O(1-6C alkyl), (1-6C)alkyl or (1-6C alkyl)OH], V_(n)-aryl,V_(n)-heteroaryl, V_(n)—F, V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—CF₃,V_(n)—CN, V_(n)—OR⁸, V_(n)—C(═O)R⁸, V_(n)—C(═O)OR⁸, V_(n)—OC(═O)R⁸,V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹, V_(n)—NR⁸C(═O)R⁹, V_(n)—SR⁸,V_(n)—S(O)R⁸, V_(n)—S(O)₂R⁸, V_(n)—S(O)₂NR⁸R⁹, and (C₁-C₆ alkyl)OH; orR⁶ and R⁷ together with the atoms to which they are attached form asaturated or partially unsaturated heterocyclic ring, wherein saidheterocyclic ring optionally comprises one or more additional ringheteroatoms independently selected from N, O or S, wherein saidheterocyclic ring is optionally substituted with one or more groupsindependently selected from oxo, V_(n)—F, V_(n)—Cl, V_(n)—Br, V_(n)—I,V_(n)—OR⁸, V_(n)—C(═O)OR⁸, V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹,V_(n)—NR⁸C(═O)R⁹, V_(n)—NR⁸C(═O)NR⁹R¹⁰, C₁-C₆ alkyl, C₂-C₆ alkenyl, andC₂-C₆ alkynyl; R⁸, R⁹ and R¹⁰ are independently H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, saturated and partially unsaturated C₃-C₆cycloalkyl, saturated and partially unsaturated C₁-C₆ heterocyclyl, arylor heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl and heteroaryl are optionally substituted with one ormore groups independently selected from oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, saturated and partially unsaturated C₃-C₆ cycloalkyl,saturated and partially unsaturated C₁-C₆ heterocyclyl, V_(n)-aryl,V_(n)-heteroaryl, V_(n)—F, V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—OR^(a),V_(n)—NR^(a)R^(b), V_(n)—C(═O)OR^(a), V_(n)—C(═O)NR^(a)R^(b), andV_(n)—NR^(a)C(═O)R^(b), or R⁸ and R⁹ together with the atoms to whichthey are attached form a saturated or partially unsaturated heterocyclicring, wherein said heterocyclic ring optionally comprises one or moreadditional ring heteroatoms independently selected from N, O or S,wherein said heterocyclic ring is optionally substituted with one ormore groups independently selected from oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, V_(n)—F, V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—OR^(a), andV_(n)—CN, or R⁹ and R¹⁰ together with the atoms to which they areattached form a saturated or partially unsaturated heterocyclic ring,wherein said heterocyclic ring optionally comprises one or moreadditional ring heteroatoms independently selected from N, O or S,wherein said heterocyclic ring is optionally substituted with one ormore groups independently selected from oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, V_(n)—F, V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—OR^(a), andV_(n)—CN; R¹¹ is H; R¹² and R¹³ are independently H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, saturated and partially unsaturated C₃-C₆cycloalkyl, saturated and partially unsaturated C₁-C₆ heterocyclyl,CH₂-heterocyclyl, aryl, heteroaryl, (1-3C alkyl)heteroaryl,(CH₂)_(n)(CR^(x)R^(y))C(O)NR⁸R⁹, (CH₂)_(n)(CR^(x)R^(y))C(O)NH—N═CHNR⁸R⁹,F, Cl, Br, I, CF₃, CN, OR⁶, C(═O)R⁶, C(═O)OR⁶, OC(═O)R⁶, C(═O)NR⁶R⁷,NR⁶R⁷, NR⁶C(═O)R⁷, SR⁶, S(O)R⁶, S(O)₂R⁶, wherein said alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionallysubstituted with one or more groups independently selected from oxo,V_(n)—F, V_(n)—Cl, V_(n)—Br, V_(n)—I, V_(n)—CF₃, V_(n)—CN, V_(n)—OR⁸,V_(n)—C(═O)OR⁸, V_(n)—OC(═O)R⁸, V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹,V_(n)—NR⁸C(═O)R⁹, C(O)(C₁-C₆ alkyl), C(O)-heterocycle [optionallysubstituted with O—(C₁-C₆ alkyl], SR^(a), SO₂R^(f), SO₂NR^(c)R^(e),C(O)(C₁-C₆ alkyl)NR^(c)R^(d), C(O)(C₁-C₆ alkyl)OR^(c), C(O)CH₂C(O)(C₁-C₆alkyl), C(═O)CHR^(g)NHC(═O)(C₁-C₆ alkyl), C(═O)CH₂C(═O)(C₁-C₆ alkyl),C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturated and partiallyunsaturated C₃-C₆ cycloalkyl, saturated and partially unsaturated C₁-C₆heterocyclyl, V_(n)-aryl, and V_(n)-heteroaryl, wherein saidheterocyclyl is optionally substituted with one or more oxo, or R¹² andR¹³ together with the atoms to which they are attached form a saturated,partially unsaturated or aromatic carbocyclic or heterocyclic ring,wherein said carbocyclic and heterocyclic rings are optionallysubstituted with one or more groups independently selected from C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturated and partially unsaturatedC₃-C₆ cycloalkyl, saturated and partially unsaturated C₁-C₆heterocyclyl, aryl, heteroaryl, oxo, F, Cl, Br, I, CF₃, CN, OR⁶,C(═O)R⁶, C(═O)OR⁶, OC(═O)R⁶, C(═O)NR⁶R⁷, NR⁶R⁷, NR⁶C(═O)R⁷, SR⁶, S(O)R⁶,S(O)₂R⁶ and SO₂NR⁶R⁷, wherein said alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl and heteroaryl are optionally substituted with one ormore groups independently selected from oxo, V_(n)—F, V_(n)—Cl,V_(n)—Br, V_(n)—I, V_(n)—CF₃, V_(n)—CN, V_(n)—OR⁸, V_(n)—C(═O)OR⁸,V_(n)—OC(═O)R⁸, V_(n)—C(═O)NR⁸R⁹, V_(n)—NR⁸R⁹, V_(n)—NR⁸C(═O)R⁹, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, saturated and partially unsaturatedC₃-C₆ cycloalkyl, saturated and partially unsaturated C₁-C₆heterocyclyl, V_(n)-aryl, and V_(n)-heteroaryl; R¹⁴ is H, methyl, ethylor OH; R^(a) and R^(b) are independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, saturated and partially unsaturated V_(n)—C₃-C₆cycloalkyl, saturated and partially unsaturated V_(n)—C₁-C₆heterocyclyl, V_(n)-aryl, or V_(n)-heteroaryl, wherein said alkyl,alkenyl, alkynyl, saturated or partially unsaturated V_(n)-cycloalkyl,saturated or partially unsaturated V_(n)-heterocyclyl, V_(n)-aryl, andV_(n)-heteroaryl are optionally substituted with one or more OH; eachR^(c), R^(e) and R^(g) is independently H or C₁-C₆ alkyl; R^(d) is H,C₁-C₆ alkyl or C(O)O(C₁-C₆ alkyl); R^(f) is C₁-C₆ alkyl or (C₁-C₆alkyl)NH₂; R^(x) is H or C₁-C₆ alkyl; R^(y) is H, C₁-C₆ alkyl, or—O(C₁-C₆ alkyl); V is alkylene having from 1 to 12 carbons, oralkenylene or alkynylene each having from 2 to 12 carbons, wherein saidalkylene, alkenylene, or alkynylene are optionally substituted with oneor more groups independently selected from C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, saturated and partially unsaturated C₃-C₆ cycloalkyl,saturated and partially unsaturated C₁-C₆ heterocyclyl, aryl,heteroaryl, F, Cl, Br, I, CF₃, cyano, OR⁸, C(═O)OR⁸, OC(═O)R⁸,C(═O)NR⁸R⁹, NR⁸R⁹, (C₁-C₆ alkyl)NR^(c)R^(e), and NR⁸C(═O)R⁹; and n is 0or 1.